Tyrosine kinase inhibitors

ABSTRACT

The present invention relates to 5H-benzo[4,5]cyclohepta[1,2-b]pyridine compounds, that are useful for treating cellular proliferative diseases, for treating disorders associated with MET activity, and for inhibiting the receptor tyrosine kinase MET. The invention also related to compositions which comprise these compounds, and methods of using them to treat cancer in mammals.

BACKGROUND OF THE INVENTION

This invention relates to 5H-benzo[4,5]cyclohepta[1,2-b]pyridinecompounds that are inhibitors of tyrosine kinases, in particular thereceptor tyrosine kinase MET, and are useful in the treatment ofcellular proliferative diseases, for example cancer, hyperplasias,restenosis, cardiac hypertrophy, immune disorders and inflammation.

Studies on signal transduction pathways have generated various promisingmolecular targets for therapeutic inhibition in cancer therapy. Receptortyrosine kinases (RTK) represent an important class of such therapeutictargets. Recently, members of the MET proto-oncogene family, a subfamilyof receptortyrosine kinases, have drawn special attention to theassociation between invasion and metastasis. The MET family, includingMET (also referred to as c-Met) and RON receptors, can function asoncogenes like most tyrosine kinases. MET has been shown to beoverexpressed and/or mutated in a variety of malignancies. A number ofMET activating mutations, many of which are located in the tyrosinekinase domain, have been detected in various solid tumors and have beenimplicated in invasion and metastasis of tumor cells.

The c-Met proto-oncogene encodes the MET receptor tyrosine kinase. TheMET receptor is a 190 kDa glycosylated dimeric complex composed of a 50kDa alpha chain disulfide-linked to a 145 kDa beta chain. The alphachain is found extracellularly while the beta chain containsextracellular, transmembrane and cytosolic domains. MET is synthesizedas a precursor and is proteolytically cleaved to yield mature alpha andbeta subunits. It displays structural similarities to semaphoring andplexins, a ligand-receptor family that is involved in cell-cellinteraction.

The natural ligand for MET is hepatocyte growth factor (HGF), adisulfide linked heterodimeric member of the scatter factor family thatis produced predominantly by mesenchymal cells and acts primarily onMET-expressing epithelial and endothelial cells in an endocrine and/orparaendocrine fashion. HGF has some homology to plasminogen.

It is known that stimulation of MET via hepatocyte growth factor (alsoknown as scatter factor, HGF/SF) results in a plethora of biological andbiochemical effects in the cell. Activation of c-Met signaling can leadto a wide array of cellular responses including proliferation, survival,angiogenesis, wound healing, tissue regeneration, scattering, motility,invasion and branching morphogenesis. HGF/MET signaling also plays amajor role in the invasive growth that is found in most tissues,including cartilage, bone, blood vessels, and neurons.

Various c-Met mutations have been well described in multiple solidtumors and some hematologic malignancies. The prototypic c-Met mutationexamples are seen in hereditary and sporadic human papillary renalcarcinoma (Schmidt, L. et al., Nat. Tenet. 1997, 16, 68-73; Jeffers, M.et al., Proc. Nat. Acad. Sci. 1997, 94, 11445-11500). Other reportedexamples of c-Met mutations include ovarian cancer, childhoodhepatocellular carcinoma, metastatic head and neck squamous cellcarcinomas and gastric cancers. HGF/MET has been shown to inhibitanoikis, suspension-induced programmed cell death (apoptosis), in headand neck squamous cell carcinoma cells.

MET signaling is implicated in various cancers, especially renal. Thenexus between MET and colorectal cancer has also been established.Analysis of c-Met expression during colorectal cancer progression showedthat 50% of the carcinoma specimens analyzed expressed 5-50-fold higherlevels of MET mRNA transcripts and protein versus the adjacent normalcolonic mucosa. In addition, when compared to the primary tumor, 70% ofcolorectal cancer liver metastasis showed MET overexpression.

MET is also implicated in glioblastoma. High-grade malignant gliomas arethe most common cancers of the central nervous system. Despite treatmentwith surgical resection, radiation therapy, and chemotherapy, the meanoverall survival is <1.5 years, and few patients survive for >3 years.Human malignant gliomas frequently express both HGF and MET, which canestablish an autocrine loop of biological significance. Glioma METexpression correlates with glioma grade, and an analysis of human tumorspecimens showed that malignant gliomas have a 7-fold higher HGF contentthan low-grade gliomas. Multiple studies have demonstrated that humangliomas frequently co-express HGF and MET and that high levels ofexpression are associated with malignant progression. It was furthershown that HGF-MET is able to activate Akt and protect glioma cell linesfrom apoptotic death, both in vitro and in vivo.

RON shares a similar structure, biochemical features, and biologicalproperties with MET. Studies have shown RON overexpression in asignificant fraction of breast carcinomas and colorectaladenocarcinomas, but not in normal breast epithelia or benign lesions.Cross-linking experiments have shown that RON and MET form anon-covalent complex on the cell surface and cooperate in intracellularsignaling. RON and MET genes are significantly co-expressed in ovariancancer cell motility and invasiveness. This suggests that co-expressionof these two related receptors might confer a selective advantage toovarian carcinoma cells during either tumor onset or progression.

A number of reviews on MET and its function as an oncogene have recentlybeen published: Cancer and Metastasis Review 22:309-325 (2003); NatureReviews/Molecular Cell Biology 4:915-925 (2003); Nature Reviews/Cancer2:289-300 (2002).

Since dysregulation of the HGF/MET signaling has been implicated as afactor in tumorgenesis and disease progression in many tumors, differentstrategies for therapeutic inhibition of this important RTK moleculeshould be investigated. Specific small molecule inhibitors againstHGF/MET signaling and against RON/MET signaling have importanttherapeutic value for the treatment of cancers in which Met activitycontributes to the invasive/metastatic phenotype.

SUMMARY OF THE INVENTION

The present invention relates to 5H-benzo[4,5]cyclohepta[1,2-b]pyridinederivatives, that are useful for treating cellular proliferativediseases, for treating disorders associated with MET activity, and forinhibiting the receptor tyrosine kinase MET. The compounds of theinvention may be illustrated by the Formula I:

DETAILED DESCRIPTION OF THE INVENTION

The compounds of this invention are useful in the inhibition of tyrosinekinses, in particular the receptor tyrosine kinase MET, and areillustrated by a compound of Formula I:

or pharmaceutically acceptable salts thereof, wherein:a dashed line represents an optional double bond;a is independently 0 or 1;b is independently 0 or 1;m is independently 0, 1, or 2;

R¹ is selected from halogen, aryl, heterocyclyl, —C(═O)NR¹⁰R¹¹,(C═O)OC₁-C₆ alkyl and NR¹⁰R¹¹; said alkyl, aryl and heterocyclyl groupoptionally substituted with one to five substituents, each substituentindependently selected from R⁸;

R² and R³ are independently selected from hydrogen, OH, —O—C₁₋₆ alkyl,—O—C(═O)C₁₋₆ alkyl, —O-aryl and NR¹⁰R¹¹, each alkyl and aryl optionallysubstituted with one to five substituents, each substituentindependently selected from R⁸; or

R² and R³ are combined to form ═O or ═N—OR^(c);

R⁴, R⁶ and R⁷ are each independently hydrogen, halogen, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, OH, —O—C₁₋₆alkyl, —O—C(═O)C₁₋₆ alkyl, —O-aryl,S(O)_(m)R^(a) and NR¹⁰R¹¹, each alkyl and aryl optionally substitutedwith one to five substituents, each substituent independently selectedfrom R⁸;

R^(7a) and R^(7b) are each independently hydrogen, halogen, C₁₋₆alkyl,OH, —O—C₁₋₆alkyl, —O—C(═O)C₁₋₆ alkyl, —O-aryl, NO₂ and NR¹⁰R¹¹, eachalkyl and aryl optionally substituted with one to five substituents,each substituent independently selected from R⁸;

R⁵ is selected from hydrogen, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, OH,—O—C₁₋₆alkyl, —O—C(═O)C₁₋₆ alkyl, —O-aryl, S(O)_(m)R^(a), —C(═O)NR¹⁰R¹¹,—NHS(O)₂NR¹⁰R¹¹ and NR¹⁰R¹¹, each alkyl, alkenyl, alkynyl and aryloptionally substituted with one to five substituents, each substituentindependently selected from R⁸;

provided that at least one of R⁴, R⁵ and R⁶ is not hydrogen;

R⁸ independently is:

1) (C═O)_(a)O_(b)C₁-C₁₀ alkyl,

2) (C═O)_(a)O_(b)aryl,

3) C₂-C₁₀ alkenyl,

4) C₂-C₁₀ alkynyl,

5) (C═O)_(a)O_(b) heterocyclyl,

6) CO₂H,

7) halo,

8) CN,

9) OH,

10) O_(b)C₁-C₆ perfluoroalkyl,

11) O_(a)(C═O)_(b)NR¹⁰R¹¹,

12) S(O)_(m)R^(a),

13) S(O)₂NR¹⁰R¹¹,

14) OS(═O)R^(a),

15) oxo,

16) CHO,

17) (N═O)R¹⁰R¹¹,

18) (C═O)_(a)O_(b)C₃-C₈ cycloalkyl,

19) O_(b)SiR^(a) ₃, or

20) NO₂;

said alkyl, aryl, alkenyl, alkynyl, heterocyclyl, and cycloalkyloptionally substituted with one, two or three substituents selected fromR⁹;

two R⁸s, attached to the same carbon atom are combined to form—(CH₂)_(u)— wherein u is 3 to 6 and one or two of the carbon atoms isoptionally replaced by a moiety selected from O, S(O)_(m),—N(R^(a))C(O)—, —N(R^(b))— and —N(COR^(a))—;

R⁹ is independently selected from:

1) (C═O)_(a)O_(b)(C₁-C₁₀)alkyl,

2) O_(b)(C₁-C₃)perfluoroalkyl,

3) oxo,

4) OH,

5) halo,

6) CN,

7) (C₂-C₁₀)alkenyl,

8) (C₂-C₁₀)alkynyl,

9) (C═O)_(a)O_(b)(C₃-C₆)cycloalkyl,

10) (C═O)_(a)O_(b)(C₀-C₆)alkylene-aryl,

11) (C═O)_(a)O_(b)(C₀-C₆)alkylene-heterocyclyl,

12) (C═O)_(a)O_(b)(C₀-C₆)alkylene-N(R^(b))₂,

13) C(O)R_(a),

14) (C₀-C₆)alkylene-CO₂R^(a),

15) C(O)H,

16) (C₀-C₆)alkylene-CO₂H,

17) C(O)N(R^(b))₂,

18) S(O)_(m)R^(a), and

19) S(O)₂NR¹⁰R¹¹;

said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl isoptionally substituted with one, two or three substituents selected fromR^(b), OH, (C₁-C₆)alkoxy, halogen, CO₂H, CN, O(C═O)C₁-C₆ alkyl, oxo, andN(R^(b))₂; or

two R⁹s, attached to the same carbon atom are combined to form—(CH₂)_(u)— wherein u is 3 to 6 and one or two of the carbon atoms isoptionally replaced by a moiety selected from O, S(O)_(m),—N(R^(a))C(O)—, —N(R^(b))— and —N(COR^(a))—;

R¹⁰ and R¹¹ are independently selected from:

1) H,

2) (C═O)O_(b)C₁-C₁₀ alkyl,

3) (C═O)O_(b)C₃-C₈ cycloalkyl,

4) (C═O)O_(b)aryl,

5) (C═O)O_(b)heterocyclyl,

6) C₁-C₁₀ alkyl,

7) aryl,

8) C₂-C₁₀ alkenyl,

9) C₂-C₁₀ alkynyl,

10) heterocyclyl,

11) C₃-C₈ cycloalkyl,

12) SO₂R^(a), and

13) (C═O)NR^(b) ₂,

said alkyl, cycloalkyl, aryl, heterocylyl, alkenyl, and alkynyl isoptionally substituted with one, two or three substituents selected fromR⁸, or

R¹⁰ and R¹¹ can be taken together with the nitrogen to which they areattached to form a monocyclic or bicyclic heterocycle with 5-7 membersin each ring and optionally containing, in addition to the nitrogen, oneor two additional heteroatoms selected from N, O and S, said monocyclicor bicyclic heterocycle optionally substituted with one, two or threesubstituents selected from R⁹;

R^(a) is independently selected from: (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₃-C₆)cycloalkyl, aryl, —(C₁-C₆)alkylenearyl, heterocyclyl and—(C₁-C₆)alkyleneheterocyclyl;

R^(b) is independently selected from: H, (C₁-C₆)alkyl, aryl,—(C₁-C₆)alkylenearyl, heterocyclyl, —(C₁-C₆)alkyleneheterocyclyl,(C₃-C₆)cycloalkyl, (C═O)OC₁-C₆ alkyl, (C═O)C₁-C₆ alkyl or S(O)₂R^(a);and

R^(c) is independently selected from: H, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₃-C₆)cycloalkyl, aryl, —(C₁-C₆)alkylenearyl, heterocyclyl and—(C₁-C₆)alkyleneheterocyclyl;

but excluding compounds represented by the following exclusion table(R^(7a) and R^(7b) are H): R¹ R² R³ R⁴ R⁵ R⁶ R⁷ Dashed line Ph Form = 0H H H Br double bond Ph Form = 0 H H H H double bond Ph Form = 0 H Br HH double bond Ph Form = 0 H H H Cl double bond Cl Form = 0 H H H Brdouble bond Ph H OH H H H

double bond Ph Form = 0 H H H

double bond Ph H H H H H oxazolyl absent

Another embodiment of the present invention is illustrated by a compoundof Formula II:

or pharmaceutically acceptable salts thereof, whereina is independently 0 or 1;b is independently 0 or 1;m is independently 0, 1, or 2;

R¹ is selected from aryl, heterocyclyl and NR¹⁰R¹¹; said aryl andheterocyclyl group optionally substituted with one to five substituents,each substituent independently selected from R⁸;

R⁴ and R⁶ are each independently hydrogen, halogen, C₁₋₆alkyl, OH,—O—C₁₋₆alkyl, —O—C(═O)C₁₋₆ alkyl, —O-aryl and NR¹⁰R¹¹, each alkyl andaryl optionally substituted with one to five substituents, eachsubstituent independently selected from R⁸;

R⁵ is selected from hydrogen, C₁₋₆alkyl, C₂₋₆ alkenyl, OH, —O—C₁₋₆alkyl,—O—C(═O)C₁₋₆ alkyl, —O-aryl, S(O)_(m)R^(a), —C(═O)NR¹⁰R¹¹,—NHS(O)₂NR¹⁰R¹¹ and NR¹⁰R¹¹, each alkyl, alkenyl and aryl optionallysubstituted with one to five substituents, each substituentindependently selected from R⁸;

provided that one of R⁴, R⁵ and R⁶ are not hydrogen;

R⁸ independently is:

1) (C═O)_(a)O_(b)C₁-C₁₀ alkyl,

2) (C═O)_(a)O_(b)aryl,

3) C₂-C₁₀ alkenyl,

4) C₂-C₁₀ alkynyl,

5) (C═O)_(a)O_(b) heterocyclyl,

6) CO₂H,

7) halo,

8) CN,

9) OH,

10) O_(b)C₁-C₆ perfluoroalkyl,

11) O_(a)(C═O)_(b)NR¹⁰R¹¹,

12) S(O)_(m)R^(a),

13) S(O)₂NR¹⁰R¹¹,

14) OS(═O)R^(a),

15) oxo,

16) CHO,

17) (N═O)R¹⁰R¹¹, or

18) (C═O)_(a)O_(b)C₃-C₈ cycloalkyl,

said alkyl, aryl, alkenyl, alkynyl, heterocyclyl, and cycloalkyloptionally substituted with one, two or three substituents selected fromR⁹; or

two R⁸s, attached to the same carbon atom are combined to form—(CH₂)_(u)— wherein u is 3 to 6 and one or two of the carbon atoms isoptionally replaced by a moiety selected from O, S(O)_(m),—N(R^(a))C(O)—, —N(R^(b))— and —N(COR^(a))—;

R⁹ is independently selected from:

1) (C═O)_(a)O_(b)(C₁-C₁₀)alkyl,

2) O_(b)(C₁-C₃)perfluoroalkyl,

3) oxo,

4) OH,

5) halo,

6) CN,

7) (C₂-C₁₀)alkenyl,

8) (C₂-C₁₀)alkynyl,

9) (C═O)_(a)O_(b)(C₃-C₆)cycloalkyl,

10) (C═O)_(a)O_(b)(C₀-C₆)alkylene-aryl,

11) (C═O)_(a)O_(b)(C₀-C₆)alkylene-heterocyclyl,

12) (C═O)_(a)O_(b)(C₀-C₆)alkylene-N(R_(b))₂,

13) C(O)R^(a),

14) (C₀-C₆)alkylene-CO₂R^(a),

15) C(O)H,

16) (C₀-C₆)alkylene-CO₂H,

17) C(O)N(R^(b))₂,

18) S(O)_(m)R^(a), and

19) S(O)₂NR¹⁰R¹¹;

said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl isoptionally substituted with one, two or three substituents selected fromR^(b), OH, (C₁-C₆)alkoxy, halogen, CO₂H, CN, O(C═O)C₁-C₆ alkyl, oxo, andN(R^(b))₂; or

R¹⁰ and R¹¹ are independently selected from:

1) H,

2) (C═O)O_(b)C₁-C₁₀ alkyl,

3) (C═O)O_(b)C₃-C₈ cycloalkyl,

4) (C═O)O_(b)aryl,

5) (C═O)O_(b)heterocyclyl,

6) C₁-C₁₀ alkyl,

7) aryl,

8) C₂-C₁₀ alkenyl,

9) C₂-C₁₀ alkynyl,

10) heterocyclyl,

11) C₃-C₈ cycloalkyl,

12) SO₂R^(a), and

13) (C═O)NR^(b) ₂,

said alkyl, cycloalkyl, aryl, heterocylyl, alkenyl, and alkynyl isoptionally substituted with one, two or three substituents selected fromR⁸, or

R¹⁰ and R¹¹ can be taken together with the nitrogen to which they areattached to form a monocyclic or bicyclic heterocycle with 5-7 membersin each ring and optionally containing, in addition to the nitrogen, oneor two additional heteroatoms selected from N, O and S, said monocyclicor bicyclic heterocycle optionally substituted with one, two or threesubstituents selected from R⁹;

R^(a) is independently selected from: (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₃-C₆)cycloalkyl, aryl, —(C₁-C₆)alkylenearyl, heterocyclyl and—(C₁-C₆)alkyleneheterocyclyl; and

R^(b) is independently selected from: H, (C₁-C₆)alkyl, aryl,—(C₁-C₆)alkylenearyl, heterocyclyl, —(C₁-C₆)alkyleneheterocyclyl,(C₃-C₆)cycloalkyl, (C═O)OC₁-C₆ alkyl, (C═O)C₁-C₆ alkyl or S(O)₂R^(a).

A further embodiment of the present invention is illustrated by acompound of Formula III:

or a pharmaceutically acceptable salt or stereoisomer thereof, whereina is independently 0 or 1;b is independently 0 or 1;m is independently 0, 1, or 2;

R¹ is selected from aryl, heterocyclyl and NR¹⁰R¹¹; said aryl andheterocyclyl group optionally substituted with one to five substituents,each substituent independently selected from R⁸;

R⁵ is selected from hydrogen, C₁₋₆alkyl, C₂₋₆ alkenyl, OH, —O—C₁₋₆alkyl,—O—C(═O)C₁₋₆ alkyl, —O-aryl, S(O)_(m)R^(a), —C(═O)NR¹⁰R¹¹,—NHS(O)₂NR¹⁰R¹¹ and NR¹⁰R¹¹, each alkyl, alkenyl and aryl optionallysubstituted with one to five substituents, each substituentindependently selected from R⁸;

R⁸ independently is:

1) (C═O)_(a)O_(b)C₁-C₁₀ alkyl,

2) (C═O)_(a)O_(b)aryl,

3) C₂-C₁₀ alkenyl,

4) C₂-C₁₀ alkynyl,

5) (C═O)_(a)O_(b) heterocyclyl,

6) CO₂H,

7) halo,

8) CN,

9) OH,

10) O_(b)C₁-C₆ perfluoroalkyl,

11) O_(a)(C═O)_(b)NR¹⁰R¹¹,

12) S(O)_(m)R^(a),

13) S(O)₂NR¹⁰R¹¹,

14) OS(═O)R^(a),

15) oxo,

16) CHO,

17) (N═O)R¹⁰R¹¹, or

18) (C═O)_(a)O_(b)C₃-C₈ cycloalkyl,

said alkyl, aryl, alkenyl, alkynyl, heterocyclyl, and cycloalkyloptionally substituted with one, two or three substituents selected fromR⁹;

R⁹ is independently selected from:

1) (C═O)_(a)O_(b)(C₁-C₁₀)alkyl,

2) O_(b)(C₁-C₃)perfluoroalkyl,

3) oxo,

4) OH,

5) halo,

6) CN,

7) (C₂-C₁₀)alkenyl,

8) (C₂-C₁₀)alkynyl,

9) (C═O)_(a)O_(b)(C₃-C₆)cycloalkyl,

10) (C═O)_(a)O_(b)(C₀-C₆)alkylene-aryl,

11) (C═O)_(a)O_(b)(C₀-C₆)alkylene-heterocyclyl,

12) (C═O)_(a)O_(b)(C₀-C₆)alkylene-N(R^(b))₂,

13) C(O)R^(a),

14) (C₀-C₆)alkylene-CO₂R^(a),

15) C(O)H,

16) (C₀-C₆)alkylene-CO₂H, and

17) C(O)N(R^(b))₂,

18) S(O)_(m)R^(a), and

19) S(O)₂NR¹⁰R¹¹;

said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl isoptionally substituted with one, two or three substituents selected fromR^(b), OH, (C₁-C₆)alkoxy, halogen, CO₂H, CN, O(C═O)C₁-C₆ alkyl, oxo, andN(R^(b))₂;

R¹⁰ and R¹¹ are independently selected from:

1) H,

2) (C═O)O_(b)C₁-C₁₀ alkyl,

3) (C═O)O_(b)C₃-C₈ cycloalkyl,

4) (C═O)O_(b)aryl,

5) (C═O)O_(b)heterocyclyl,

6) C₁-C₁₀ alkyl,

7) aryl,

8) C₂-C₁₀ alkenyl,

9) C₂-C₁₀ alkynyl,

10) heterocyclyl,

11) C₃-C₈ cycloalkyl,

12) SO₂R^(a), and

13) (C═O)NR^(b) ₂,

said alkyl, cycloalkyl, aryl, heterocylyl, alkenyl, and alkynyl isoptionally substituted with one, two or three substituents selected fromR⁸, or

R¹⁰ and R¹¹ can be taken together with the nitrogen to which they areattached to form a monocyclic or bicyclic heterocycle with 5-7 membersin each ring and optionally containing, in addition to the nitrogen, oneor two additional heteroatoms selected from N, O and S, said monocyclicor bicyclic heterocycle optionally substituted with one, two or threesubstituents selected from R⁹;

R^(a) is independently selected from: (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₃-C₆)cycloalkyl, aryl, —(C₁-C₆)alkylenearyl, heterocyclyl and—(C₁-C₆)alkyleneheterocyclyl; and

R^(b) is independently selected from: H, (C₁-C₆)alkyl, aryl,—(C₁-C₆)alkylenearyl, heterocyclyl, —(C₁-C₆)alkyleneheterocyclyl,(C₃-C₆)cycloalkyl, (C═O)OC₁-C₆ alkyl, (C═O)C₁-C₆ alkyl or S(O)₂R^(a).

Specific examples of the compounds of the instant invention include:

-   7-bromo-3-chloro-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;-   6-bromo-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;-   8-bromo-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;-   3-chloro-7-[(2,4-dimethoxybenzyl)amino]-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;-   7-amino-3-chloro-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;-   N-(3-chloro-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)methanesulfonamide;-   6-(methylthio)-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;-   6-(methylsulfonyl)-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;-   Methyl    5-oxo-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-7-carboxylate;-   6-methyl-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;-   3-phenyl-7-[(trimethylsilyl)ethynyl]-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;-   3-phenyl-7-vinyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;-   7-ethyl-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;-   N-(5-oxo-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)acetamide;-   3-chloro-7-hydroxy-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;-   7-[(2,4-dimethoxybenzyl)amino]-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;-   6-amino-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;-   7-amino-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;-   8-amino-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;-   9-amino-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;-   2-hydroxy-N-(5-oxo-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)propanamide;-   3-phenyl-7-(pyridin-2-ylamino)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;-   7-[(3-methoxypropyl)amino]-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;-   7-[(2-methoxyethyl)amino]-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;-   7-[(3-methoxypropyl)amino]-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-ol;-   7-[(2-methoxyethyl)amino]-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;-   3-phenyl-7-[(2,2,2-trifluoroethyl)amino]-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;-   5-oxo-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-7-carboxylic    acid;-   N-methyl-5-oxo-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-7-carboxamide;-   7-methyl-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;-   8-methyl-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;-   9-methyl-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;-   7-ethynyl-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;-   3-phenyl-7-[(1E/Z)-prop-1-en-1-yl]-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;-   3-phenyl-7-propyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;-   7-isobutyl-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;-   9-(methylthio)-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;-   7-(methylthio)-3-phenyl-10,11-dihydro-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;-   9-(methylsulfonyl)-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;-   6-methoxy-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;-   N-(5-oxo-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)methanesulfonamide;-   N′-(3-chloro-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)-N,N-dimethylsulfamide;-   N-benzyl-N′-(3-chloro-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)-N-methylsulfamide;-   N-(3-chloro-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)-1,1,1-trifluoromethanesulfonamide;-   3-chloro-7-{[(3-methylpyridin-4-yl)methyl]amino}-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;-   N′-(3-chloro-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)-N-(isoxazol-3-ylmethyl)-N-methylsulfamide;-   N-(3-chloro-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)-N′-[(1-morpholin-4-ylcyclopentyl)methyl]sulfamide;-   3,7-bis[(pyridin-3-ylmethyl)amino]-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;-   3-chloro-7-[(pyridin-2-ylmethyl)amino]-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;-   N-[5-oxo-3-(3-thienyl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;-   7-[(2,4-dimethoxybenzyl)amino]-3-(1-methyl-1H-pyrazol-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;-   7-(isopropylamino)-3-(1-methyl-1H-pyrazol-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;-   3-chloro-7-{[(3-methylpyridin-2-yl)methyl]amino}-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;-   3-(1-methyl-1H-pyrazol-4-yl)-7-{[(3-methylpyridin-2-yl)methyl]amino}-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;-   N′-(3-chloro-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)-N-((2R)-1,4-dioxan-2-ylmethyl)-N-methylsulfamide;-   N′-(3-chloro-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)-N-((2S)-1,4-dioxan-2-ylmethyl)-N-methylsulfamide;-   N′-(3-chloro-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)-N-(1,4-dioxan-2-ylmethyl)-N-methylsulfamide;-   N-((2R)-1,4-dioxan-2-ylmethyl)-N-methyl-N′-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]sulfamide;-   N-((2S)-1,4-dioxan-2-ylmethyl)-N-methyl-N′-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]sulfamide;-   N-(1,4-dioxan-2-ylmethyl)-N-methyl-N′-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]sulfamide;-   N-methyl-N′-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-({3R}-tetrahydrofuran-3-yl)sulfamide;-   N-methyl-N′-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-({3S}-tetrahydrofuran-3-yl)sulfamide;-   N-methyl-N′-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-(tetrahydrofuran-3-yl)sulfamide;-   N-[3-(4-chlorophenyl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;-   N-[3-(2-chlorophenyl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;-   N-(5-oxo-3-pyridin-4-yl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)methanesulfonamide;-   N-(5-oxo-3-pyridin-3-yl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)methanesulfonamide;-   N-[5-oxo-3-(1H-pyrazol-3-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;-   N-[3-(3-chlorophenyl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;-   N-(5-oxo-3-pyrimidin-5-yl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)methanesulfonamide;-   N-(5-oxo-3-quinolin-6-yl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)methanesulfonamide;-   N-[3-(3-furyl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;-   N-[3-(2-furyl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;-   N-[3-(4-fluorophenyl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;-   N-[3-(3-fluorophenyl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;-   N-[3-(2-fluorophenyl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;-   N-(5-oxo-3-quinolin-8-yl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)methanesulfonamide;-   N-(5-oxo-3-quinolin-3-yl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)methanesulfonamide;-   N-(5-oxo-3-quinolin-5-yl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)methanesulfonamide;-   N-[3-(2,4-dichlorophenyl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;-   N-(3-imidazo[1,2-a]pyrazin-3-yl-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)methanesulfonamide;-   N-[5-oxo-3-(1,3-thiazol-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;-   N-(3-isothiazol-4-yl-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)methanesulfonamide;-   N-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;-   N-(3-isothiazol-5-yl-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)methanesulfonamide;-   N-[3-(3,5-dimethylisoxazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;-   N-[5-oxo-3-(1H-pyrazol-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;-   methyl    (4-{7-[(methylsulfonyl)amino]-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-3-yl}-1H-pyrazol-1-yl)acetate;-   ethyl    3-(4-{7-[(methylsulfonyl)amino]-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-3-yl}-1H-pyrazol-1-yl)propanoate;-   N-(3-{1-[2-(dimethylamino)ethyl]-1H-pyrazol-4-yl}-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)methanesulfonamide;-   N-[3-(1-isobutyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;-   N-[5-oxo-3-(1-propyl-1H-pyrazol-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;-   N-(3-{1-[3-(dimethylamino)propyl]-1H-pyrazol-4-yl}-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)methanesulfonamide;-   N-{3-[1-(2-morpholin-4-yl-2-oxoethyl)-1H-pyrazol-4-yl]-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl}methanesulfonamide;-   N-{5-oxo-3-[1-(2-pyrrolidin-1-ylethyl)-1H-pyrazol-4-yl]-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl}methanesulfonamide;-   N-[3-(1-benzyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;-   (4-{7-[(methylsulfonyl)amino]-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-3-yl}-1H-pyrazol-1-yl)acetic    acid;-   3-(4-{7-[(methylsulfonyl)amino]-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-3-yl}-1H-pyrazol-1-yl)propanoic    acid;-   N-(3-{7-[(methylsulfonyl)amino]-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-3-yl}phenyl)-3-piperidin-1-ylpropanamide;-   N-(4-{7-[(methylsulfonyl)amino]-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-3-yl}phenyl)methanesulfonamide;-   N-(3-{1-[3-(benzyloxy)propyl]-1H-pyrazol-4-yl}-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)methanesulfonamide;-   N-[3-(1-isopropyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;-   N-{3-[1-(3-methylbutyl)-1H-pyrazol-4-yl]-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl}methanesulfonamide;-   N-[3-(1-cyclopentyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;-   N-{3-[1-(3-hydroxypropyl)-1H-pyrazol-4-yl]-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl}methanesulfonamide;-   3-{7-[(methylsulfonyl)amino]-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-3-yl}benzoic    acid;-   3-(2,3-dihydro-1H-pyrazolo[1,2-a]pyrazol-4-ium-6-yl)-7-[(methylsulfonyl)amino]-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridinium    bis(trifluoroacetate);-   methyl    2-(4-{7-[(methylsulfonyl)amino]-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-3-yl}-1H-pyrazol-1-yl)propanoate;-   N-{3-[1-(3,3-dimethyl-2-oxobutyl)-1H-pyrazol-4-yl]-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl}methanesulfonamide;-   4-{7-[(methylsulfonyl)amino]-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-3-yl}benzoic    acid;-   N-[3-(3-nitrophenyl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;-   N-[3-(4-nitrophenyl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;-   N-isobutyl-3-{7-[(methylsulfonyl)amino]-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-3-yl}benzamide;-   3-{7-[(methylsulfonyl)amino]-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-3-yl}-N-(2-morpholin-4-ylethyl)benzamide;-   N-[2-(1-methylpyrrolidin-2-yl)ethyl]-3-{7-[(methylsulfonyl)amino]-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-3-yl}benzamide;-   N-[(1-methyl-1H-pyrazol-4-yl)methyl]-3-{7-[(methylsulfonyl)amino]-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-3-yl}benzamide;-   N-{3-[1-(3-hydroxypropyl)-1H-pyrazol-4-yl]-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl}methanesulfonamide;-   N-[(5-methylpyrazin-2-yl)methyl]-3-{7-[(methylsulfonyl)amino]-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-3-yl}benzamide;-   N-isobutyl-4-{7-[(methylsulfonyl)amino]-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-3-yl}benzamide;-   N-[(1-methyl-1H-pyrazol-4-yl)methyl]4-{7-[(methylsulfonyl)amino]-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-3-yl}benzamide;-   2-methyl-N-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]propane-2-sulfonamide;-   N,N-dimethyl-N′-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]sulfamide;-   N-benzyl-N-methyl-N′-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]sulfamide;-   N,N-diethyl-N′-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]sulfamide;-   N-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]pyrrolidine-1-sulfonamide;-   N-ethyl-N-methyl-N′-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]sulfamide;-   N,N-dimethyl-N′-[5-oxo-3-(1-propyl-1H-pyrazol-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]sulfamide;-   N,N-dimethyl-N′-{3-[1-(2-morpholin-4-yl-2-oxoethyl)-1H-pyrazol-4-yl]-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl}sulfamide;-   N′-(3-{1-[3-(dimethylamino)propyl]-1H-pyrazol-4-yl}-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)-N,N-dimethylsulfamide;-   N-isopropyl-N-methyl-N′-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]sulfamide;-   7-(5-methyl-1,1-dioxido-1,2,5-thiadiazolidin-2-yl)-3-(1-methyl-1H-pyrazol-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;-   N-methyl-N′-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]sulfamide;-   1,1,1-trifluoro-N-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;-   7-[(2,4-dimethoxybenzyl)amino]-3-(3-thienyl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;-   7-[(2,4-dimethoxybenzyl)amino]-3-(1H-pyrazol-3-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;-   7-[(2,4-dimethoxybenzyl)amino]-3-(5-methyl-2-thienyl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;-   3-(1-benzothien-3-yl)-7-[(2,4-dimethoxybenzyl)amino]-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;-   N-(4-{7-[(2,4-dimethoxybenzyl)amino]-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-3-yl}phenyl)acetamide;-   4-{7-[(2,4-dimethoxybenzyl)amino]-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-3-yl}benzoic    acid;-   7-amino-3-(3-thienyl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;-   7-amino-3-(2-thienyl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;-   7-amino-3-(1H-pyrazol-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;-   7-amino-3-(1-methyl-1H-pyrazol-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;    7-amino-3-(1H-pyrazol-3-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;-   7-amino-3-(5-methyl-2-thienyl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;-   7-amino-3-(1-benzothien-3-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;-   N-[4-(7-amino-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-3-yl)phenyl]acetamide;-   4-(7-amino-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-3-yl)benzoic    acid;-   7-hydroxy-3-(3-thienyl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;-   7-[(cyclohexylmethyl)amino]-3-(1-methyl-1H-pyrazol-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;-   7-[(4-fluorobenzyl)amino]-3-(1-methyl-1H-pyrazol-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;-   3-(1-methyl-1H-pyrazol-4-yl)-7-vinyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;-   7-[(2,4-difluorobenzyl)amino]-3-(1-methyl-1H-pyrazol-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;-   3-(1-methyl-1H-pyrazol-4-yl)-7-[(2-phenylethyl)amino]-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;-   7-[(3,4-difluorobenzyl)amino]-3-(1-methyl-1H-pyrazol-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;-   7-[(4-methylbenzyl)amino]-3-(1-methyl-1H-pyrazol-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;-   7-[(2,4-dimethylbenzyl)amino]-3-(1-methyl-1H-pyrazol-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;-   7-{[2-(4-fluorophenyl)ethyl]amino}-3-(1-methyl-1H-pyrazol-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;-   7-(butylamino)-3-(1-methyl-1H-pyrazol-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;-   3-(1-methyl-1H-pyrazol-4-yl)-7-(propylamino)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;-   7-[(3-methylbutyl)amino]-3-(1-methyl-1H-pyrazol-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;-   7-(isopropylamino)-3-(1-methyl-1H-pyrazol-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;-   7-[(1,3-benzodioxol-5-ylmethyl)amino]-3-(1-methyl-1H-pyrazol-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;-   7-(isobutylamino)-3-(1-methyl-1H-pyrazol-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;-   7-[(2-methylbenzyl)amino]-3-(1-methyl-1H-pyrazol-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;-   3-(1-methyl-1H-pyrazol-4-yl)-7-{[2-(trifluoromethyl)benzyl]amino}-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;-   7-[(biphenyl-2-ylmethyl)amino]-3-(1-methyl-1H-pyrazol-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;-   7-[(2-chlorobenzyl)amino]-3-(1-methyl-1H-pyrazol-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;-   7-[(2,3-dimethylbenzyl)amino]-3-(1-methyl-1H-pyrazol-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;-   N-methyl-N′-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-(tetrahydrofuran-3-yl)sulfamide;-   N′-(3-{1-[3-(benzyloxy)propyl]-1H-pyrazol-4-yl}-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)-N,N-dimethylsulfamide;-   N-{3-[1-(3-hydroxypropyl)-1H-pyrazol-4-yl]-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl}-N,N-dimethylsulfamide;-   7-[(imidazo[1,2-a]pyridin-3-ylmethyl)amino]-3-(1-methyl-1H-pyrazol-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;-   N,N-dimethyl-N′-(3-{1-[(3-methyloxetan-3-yl)methyl]-1H-pyrazol-4-yl}-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)sulfamide;-   7-{[(1-methyl-5-oxopyrrolidin-2-yl)methyl]amino}-3-(1-methyl-1H-pyrazol-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;-   3,7-bis(1-methyl-1H-pyrazol-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;-   3-(1-methyl-1H-pyrazol-4-yl)-7-(1H-pyrrol-2-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;-   3-(1-methyl-1H-pyrazol-4-yl)-7-{[(3-methylpyridin-4-yl)methyl]amino}-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;-   3-(1-methyl-1H-pyrazol-4-yl)-7-(1H-pyrazol-3-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;-   N-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-2-(trifluoromethyl)benzamide;-   7-{[(1-ethylpyrrolidin-2-yl)methyl]amino}-3-(1-methyl-1H-pyrazol-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;-   7-[(2,6-dimethylbenzyl)amino]-3-(1-methyl-1H-pyrazol-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;-   N-methyl-N-[(1-methyl-5-oxopyrrolidin-2-yl)methyl]-N′-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]sulfamide;-   N-methyl-N-[(1-methyl-1H-imidazol-2-yl)methyl]-N′-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]sulfamide;-   N-methyl-N′-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-(tetrahydro-2H-pyran-2-ylmethyl)sulfamide;-   N-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-2-(trifluoromethyl)benzene-sulfonamide;-   N-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N′-[2-(trifluoromethyl)benzyl]sulfamide;-   methyl    4-(7-{[(3-methylpyridin-2-yl)methyl]amino}-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-3-yl)benzoate;-   N-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N′-(tetrahydrofuran-3-yl)sulfamide;-   tert-butyl    4-[4-(7-{[(3-methylpyridin-2-yl)methyl]amino}-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-3-yl)phenyl]piperazine-1-carboxylate;-   7-{[(3-methylpyridin-2-yl)methyl]amino}-3-(4-piperazin-1-ylphenyl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;-   3-[3-(dimethylamino)phenyl]-7-{[(3-methylpyridin-2-yl)methyl]amino}-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;-   7-{[(3-methylpyridin-2-yl)methyl]amino}-3-pyridin-4-yl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;-   N-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N′-(tetrahydrofuran-3-ylmethyl)sulfamide;-   N-[(1-methyl-1H-pyrazol-4-yl)methyl]-N′-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]sulfamide;-   N-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]morpholine-4-sulfonamide;-   N-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-2-(trifluoromethyl)-5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-sulfonamide;-   N-isobutyl-4-(7-{[(3-methylpyridin-2-yl)methyl]amino}-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-3-yl)benzamide;-   7-{[(3-methylpyridin-2-yl)methyl]amino}-3-pyrimidin-5-yl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;-   4-(7-{[(3-methylpyridin-2-yl)methyl]amino}-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-3-yl)-N-phenylbenzamide;-   3-(6-fluoropyridin-3-yl)-7-{[(3-methylpyridin-2-yl)methyl]amino}-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;-   N-[3-(dimethylamino)propyl]4-(7-{[(3-methylpyridin-2-yl)methyl]amino}-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-3-yl)benzamide;-   3-(1-methyl-1H-pyrazol-4-yl)-7-[(tetrahydro-2H-pyran-4-ylmethyl)amino]-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;-   3-pyridin-4-yl-7-[(tetrahydro-2H-pyran-4-ylmethyl)amino]-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;-   7-[(1,4-dioxan-2-ylmethyl)amino]-3-(1-methyl-1H-pyrazol-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;-   N-[3-(4-isopropylpiperazin-1-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;-   3-(4-isopropylpiperazin-1-yl)-7-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;-   N-(5-oxo-3-piperidin-1-yl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)methanesulfonamide;-   N-(3-morpholin-4-yl-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)methanesulfonamide;-   N-(5-oxo-3-pyrrolidin-1-yl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)methanesulfonamide;-   N-[3-(benzylamino)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;-   N-{3-[(2,4-dimethoxybenzyl)amino]-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl}methanesulfonamide;-   N-{3-[butyl(methyl)amino]-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl}methanesulfonamide;-   N-{3-[(cyclopropylmethyl)amino]-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl}methanesulfonamide;-   N-(3-amino-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)methanesulfonamide;-   N,N′-(5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-3,7-diyl)dimethanesulfonamide;-   N-(3-anilino-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)methanesulfonamide;-   N-[3-(cyclohexylamino)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;-   N-[5-oxo-3-(pyridin-4-ylamino)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;-   N-[5-oxo-3-(pyridin-3-ylamino)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;-   N-[5-oxo-3-(pyridin-2-ylamino)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;-   tert-butyl    4-{7-[(methylsulfonyl)amino]-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-3-yl}piperazine-1-carboxylate;-   N-[3-(4-methylpiperazin-1-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;-   N-[3-(1,4-dioxa-8-azaspiro[4,5]dec-8-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;-   N-[5-oxo-3-(4-quinolin-2-ylpiperazin-1-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;-   N-{3-[(4-chlorobenzyl)amino]-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl}methanesulfonamide;-   N-{5-oxo-3-[(1-phenylethyl)amino]-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl}methanesulfonamide;-   N-{3-[(2-morpholin-4-ylethyl)amino]-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl}methanesulfonamide;-   N-{5-hydroxy-3-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl}methane    sulfonamide;-   N-(3-chloro-5-hydroxy-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)methanesulfonamide;-   N-(3-{4-[(2-methyl-1,3-thiazol-4-yl)methyl]piperazin-1-yl}-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)methanesulfonamide;-   N-{3-[4-(4-chloropyridin-2-yl)piperazin-1-yl]-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl}methanesulfonamide;-   N-{5-oxo-3-[4-(pyridin-3-ylmethyl)piperazin-1-yl]-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl}methanesulfonamide;-   N-(5-oxo-3-piperazin-1-yl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)methanesulfonamide;-   N-{5-oxo-3-[4-(pyridin-2-ylmethyl)piperazin-1-yl]-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl}methanesulfonamide;-   N-[5-oxo-3-(4-pyridin-3-ylpiperazin-1-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;-   N-{5-oxo-3-[2-(trifluoromethyl)-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl]-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl}methanesulfonamide;-   N-(3-{4-[3,5-bis(trifluoromethyl)phenyl]piper-azin-1-yl}-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)methanesulfonamide;-   N-{3-[(1-methyl-1H-pyrazol-3-yl)amino]-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl}methanesulfonamide;-   7-[(2,4-dimethoxybenzyl)amino]-3-(1,4-dioxa-8-azaspiro[4,5]dec-8-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;-   7-[(2,4-dimethoxybenzyl)amino]-3-(4-isopropylpiperazin-1-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;-   3-(4-isopropylpiperazin-1-yl)-7-morpholin-4-yl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;-   3-(4-acetylpiperazin-1-yl)-7-morpholin-4-yl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;-   3-(4-isopropylpiperazin-1-yl)-7-[(1-phenylethyl)amino]-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;-   7-anilino-3-(4-isopropylpiperazin-1-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;-   7-(benzylamino)-3-(4-isopropylpiperazin-1-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;-   4-[7-(benzylamino)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-3-yl]-N,N-dimethylpiperazine-1-carboxamide;-   7-(tert-butylamino)-3-(4-isopropylpiperazin-1-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;-   3-(4-isopropylpiperazin-1-yl)-7-[(2-methoxyethyl)amino]-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;-   3-(4-isopropylpiperazin-1-yl)-7-[(3-methoxypropyl)amino]-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;-   7-[(1-ethylpropyl)amino]-3-(4-isopropylpiperazin-1-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;-   7-[(1-ethylpropyl)amino]-3-(4-methyl-1,4-diazepan-1-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;-   7-[(3-methoxypropyl)amino]-3-(4-methyl-1,4-diazepan-1-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;-   7-amino-3-(4-isopropylpiperazin-1-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;-   7-amino-3-(4-oxopiperidin-1-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;-   7-hydroxy-3-(4-isopropylpiperazin-1-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;-   3-(4-isopropylpiperazin-1-yl)-7-piperidin-1-yl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;-   3,7-bis{[(3-methylpyridin-4-yl)methyl]amino}-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;-   N-(3-chloro-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)-2-methoxyacetamide;-   ethyl    (5-oxo-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-8-yl)carbamate;-   N-ethyl-N′-(5-oxo-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-8-yl)urea;-   N-(2,4-dimethoxybenzyl)-N-(5-oxo-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)ethylenesulfonamide;-   N-(5-oxo-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)ethylenesulfonamide;-   N-(5-oxo-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)-2-pyrrolidin-1-ylethanesulfonamide;-   N-methyl-N-(5-oxo-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)methanesulfonamide;-   3-chloro-7-[(2,4-dimethoxybenzyl)(methyl)amino]-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;-   dimethyl    [3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]amidophosphate;-   N,N-(5-oxo-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)bis-methanesulfonamide;-   N,N-(5-oxo-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)bis-benzenesulfonamide;-   N-(5-oxo-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)benzenesulfonamide;-   N-(5-oxo-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)ethanesulfonamide;-   N-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]propane-2-sulfonamide;-   2-chloro-N-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]propane-2-sulfinamide;-   N-(5-oxo-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)-2-phenylacetamide;-   2-methoxy-N-(5-oxo-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)acetamide;-   N-acetyl-N′-(5-oxo-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-9-yl)acetamide;-   N-[3-(4-isopropylpiperazin-1-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-2-methoxyacetamide;-   N-[3-(1,4-dioxa-8-azaspiro[4,5]dec-8-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-2-methoxyacetamide;-   2-methoxy-N-[5-oxo-3-(3-thienyl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]acetamide;-   2-{[(3-chloro-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)amino]carbonyl}benzoic    acid;-   ethyl    [3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]carbamate;-   N-ethyl-N′-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]urea;-   7-amino-3-(1,4-dioxa-8-azaspiro[4,5]dec-8-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;-   2-(diethylamino)-N-(5-oxo-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)ethanesulfonamide;-   2-morpholin-4-yl-N-(5-oxo-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)ethanesulfonamide;-   2-(1H-imidazol-1-yl)-N-(5-oxo-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)ethanesulfonamide;-   2-[(2,4-dimethoxybenzyl)amino]-N-(5-oxo-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)ethanesulfonamide;-   2-[(2-morpholin-4-ylethyl)amino]-N-(5-oxo-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)ethanesulfonamide;-   2-(benzylamino)-N-(5-oxo-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)ethanesulfonamide;-   2-(dimethylamino)-N-(5-oxo-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)ethanesulfonamide;-   N-(5-oxo-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)-2-(1H-pyrazol-1-yl)ethanesulfonamide;-   N-(3-chloro-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)-2-(1H-imidazol-1-yl)ethanesulfonamide;-   N-[3-(1,4-dioxa-8-azaspiro[4,5]dec-8-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-2-(1H-imidazol-1-yl)ethanesulfonamide;-   7-(methylamino)-3-(1-methyl-1H-pyrazol-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;-   N-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]sulfamide;-   tert-butyl    ({[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]amino}sulfonyl)carbamate;-   N-(5-hydroxy-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)methanesulfonamide;-   7-[(methylsulfonyl)amino]-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-yl    acetate;-   N-(5-methoxy-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)-N-methylmethanesulfonamide;-   N-(3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)methanesulfonamide;-   N-[(5E/Z)-5-(hydroxyimino)-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;-   N-(3-phenyl-5-pyrrolidin-1-yl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)methanesulfonamide;-   N-[(5E/Z)-5-(methoxyimino)-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;-   N-[(5E/Z)-5-(tert-butoxyimino)-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;-   (5E/Z)-7-amino-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one    oxime;-   N-[5-(dimethylamino)-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;-   N-[5-(isopropylamino)-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;-   N-[5-(cyclopropylamino)-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;-   N-[5-(benzylamino)-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;-   N-(5-azetidin-1-yl-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)methanesulfonamide;-   N-(3-phenyl-5-piperidin-1-yl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)methanesulfonamide;-   N-(5-morpholin-4-yl-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)methanesulfonamide;-   7-[(methylsulfonyl)amino]-3-phenyl-5-piperazinediium-1-yl-5H-benzo[4,5]cyclohepta[1,2-b]pyridine;-   7-(hydroxymethyl)-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-ol;-   7-({[tert-butyl(dimethyl)silyl]oxy}methyl)-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-ol;-   7-({[tert-butyl(dimethyl)silyl]oxy}methyl)-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;-   7-(hydroxymethyl)-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;-   7-({[tert-butyl(dimethyl)silyl]oxy}methyl)-3-chloro-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;-   7-({[tert-butyl(dimethyl)silyl]oxy}methyl)-3-(1-methyl-1H-pyrazol-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;-   7-(hydroxymethyl)-3-(1-methyl-1H-pyrazol-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;-   [3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methyl    acetate;-   [3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methyl    benzoate;-   7-[(methylsulfonyl)methyl]-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;-   (5-oxo-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)methyl    methanesulfinate;-   7-(aminomethyl)-3-(1-methyl-1H-pyrazol-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;-   N-{[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methyl}methanesulfonamide;-   N-(5-oxo-3-phenyl-10,11-dihydro-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)methanesulfonamide;-   7-amino-6-chloro-3-(1-methyl-1H-pyrazol-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;-   methyl    7-{[(dimethylamino)sulfonyl]amino}-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-3-carboxylate;-   7-{[(dimethylamino)sulfonyl]amino}-5-oxo-N-1,3-thiazol-2-yl-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-3-carboxamide;-   3-chloro-7-vinyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;-   3-chloro-7-oxiran-2-yl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;-   3-chloro-7-(1-hydroxyethyl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-ol;-   3-chloro-7-(2-hydroxyethyl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-ol;-   7-(1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-3-chloro-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;-   7-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-3-chloro-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;-   7-(1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-3-(1-methyl-1H-pyrazol-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;-   7-[(1R)-1-hydroxyethyl]-3-(1-methyl-1H-pyrazol-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;-   7-[(1S)-1-hydroxyethyl]-3-(1-methyl-1H-pyrazol-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;-   7-(2-hydroxyethyl)-3-(1-methyl-1H-pyrazol-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;-   3-chloro-7-(1-hydroxyethyl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;-   3-chloro-7-ethyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-ol;-   3-chloro-7-(1,2-dihydroxyethyl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;-   7-(1,2-dihydroxyethyl)-3-(1-methyl-1H-pyrazol-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;-   3-chloro-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-7-carbaldehyde;-   3-chloro-7-(1-hydroxypropyl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;-   7-[(1R)-1-methoxyethyl]-3-(1-methyl-1H-pyrazol-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;-   7-[(1S)-1-methoxyethyl]-3-(1-methyl-1H-pyrazol-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;-   tert-butyl    4-[2-(3-chloro-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)-2-hydroxyethyl]piperazine-1-carboxylate;-   tert-butyl    4-{2-hydroxy-2-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]ethyl}piperazine-1-carboxylate;-   7-(1-hydroxy-2-piperazin-1-ylethyl)-3-(1-methyl-1H-pyrazol-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;-   N′-[11-Chloro-3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N,N-dimethylsulfamide;-   7-[(2-morpholin-4-yl-2-oxoethyl)amino]-3-[1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl]-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;-   3-(1-methyl-1H-pyrazol-4-yl)-7-{[2-(3-oxomorpholin-4-yl)ethyl]amino}-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;-   3-fluoro-N-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]azetidine-1-sulfonamide;-   N-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]azetidine-1-sulfonamide;-   3-(1-methyl-1H-pyrazol-4-yl)-7-[(2-morpholin-4-yl-2-oxoethyl)amino]-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;-   N-(2-fluoro-3-methoxypropyl)-N-methyl-N′-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]sulfamide-   7-(2,2-difluoro-1-hydroxyethyl)-3-(1-methyl-1H-pyrazol-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one-   7-(2,2-difluoro-1(R)-hydroxyethyl)-3-(1-methyl-1H-pyrazol-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one-   7-(2,2-difluoro-1-hydroxyethyl)-3-(1-methyl-1H-pyrazol-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one-   7-(2,2-difluoro-1(S)-hydroxyethyl)-3-(1-methyl-1H-pyrazol-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one-   N-(1,4-dioxan-2-ylmethyl)-N′-[6-fluoro-3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-methylsulfamide;-   N-(1,4-dioxan-2-ylmethyl)-N′-[8-fluoro-3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-methylsulfamide;-   6-fluoro-7-(2-fluoro-1-hydroxyethyl)-3-(1-methyl-1H-pyrazol-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;    or a pharmaceutically acceptable salt or stereoisomer thereof.

In a further embodiment, specific examples of the compounds of theinstant invention include those compounds listed above except for thefollowing compounds:

-   7-bromo-3-chloro-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;-   6-bromo-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;-   8-bromo-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;    or a stereoisomer thereof.

The compounds of the present invention may have asymmetric centers,chiral axes, and chiral planes (as described in: E. L. Eliel and S. H.Wilen, Stereochemistry of Carbon Compounds, John Wiley & Sons, New York,1994, pages 1119-1190), and occur as racemates, racemic mixtures, and asindividual diastereomers, with all possible isomers and mixturesthereof, including optical isomers, all such stereoisomers beingincluded in the present invention. In addition, the compounds disclosedherein may exist as tautomers and both tautomeric forms are intended tobe encompassed by the scope of the invention, even though only onetautomeric structure is depicted.

When any variable (e.g. R⁷, R⁸, R^(b), etc.) occurs more than one timein any constituent, its definition on each occurrence is independent atevery other occurrence. Also, combinations of substituents and variablesare permissible only if such combinations result in stable compounds.Lines drawn into the ring systems from substituents represent that theindicated bond may be attached to any of the substitutable ring atoms.If the ring system is polycyclic, it is intended that the bond beattached to any of the suitable carbon atoms on the proximal ring only.

It is understood that substituents and substitution patterns on thecompounds of the instant invention can be selected by one of ordinaryskill in the art to provide compounds that are chemically stable andthat can be readily synthesized by techniques known in the art, as wellas those methods set forth below, from readily available startingmaterials. If a substituent is itself substituted with more than onegroup, it is understood that these multiple groups may be on the samecarbon or on different carbons, so long as a stable structure results.The phrase “optionally substituted with one or more substituents” shouldbe taken to be equivalent to the phrase “optionally substituted with atleast one substituent” and in such cases another embodiment will havefrom zero to three substituents.

As used herein, “alkyl” is intended to include both branched andstraight-chain saturated aliphatic hydrocarbon groups having thespecified number of carbon atoms. For example, C₁-C₁₀, as in “C₁-C₁₀alkyl” is defined to include groups having 1, 2, 3, 4, 5, 6, 7, 8, 9 or10 carbons in a linear or branched arrangement. For example, “C₁-C₁₀alkyl” specifically includes methyl, ethyl, n-propyl, i-propyl, n-butyl,t-butyl, i-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, and so on.The term “cycloalkyl” means a monocyclic saturated aliphatic hydrocarbongroup having the specified number of carbon atoms. For example,“cycloalkyl” includes cyclopropyl, methyl-cyclopropyl,2,2-dimethyl-cyclobutyl, 2-ethyl-cyclopentyl, cyclohexyl, and so on. Inan embodiment of the invention the term “cycloalkyl” includes the groupsdescribed immediately above and further includes monocyclic unsaturatedaliphatic hydrocarbon groups. For example, “cycloalkyl” as defined inthis embodiment includes cyclopropyl, methyl-cyclopropyl,2,2-dimethyl-cyclobutyl, 2-ethyl-cyclopentyl, cyclohexyl, cyclopentenyl,cyclobutenyl and so on.

The term “alkylene” means a hydrocarbon diradical group having thespecified number of carbon atoms. For example, “alkylene” includes—CH₂—, —CH₂CH₂— and the like.

When used in the phrases “C₁-C₆ aralkyl” and “C₁-C₆ heteroaralkyl” theterm “C₁-C₆” refers to the alkyl portion of the moiety and does notdescribe the number of atoms in the aryl and heteroaryl portion of themoiety.

“Alkoxy” represents either a cyclic or non-cyclic alkyl group ofindicated number of carbon atoms attached through an oxygen bridge.“Alkoxy” therefore encompasses the definitions of alkyl and cycloalkylabove.

If no number of carbon atoms is specified, the term “alkenyl” refers toa non-aromatic hydrocarbon radical, straight, branched or cyclic,containing from 2 to 10 carbon atoms and at least one carbon to carbondouble bond. Preferably one carbon to carbon double bond is present, andup to four non-aromatic carbon-carbon double bonds may be present. Thus,“C₂-C₆ alkenyl” means an alkenyl radical having from 2 to 6 carbonatoms. Alkenyl groups include ethenyl, propenyl, butenyl,2-methylbutenyl and cyclohexenyl. The straight, branched or cyclicportion of the alkenyl group may contain double bonds and may besubstituted if a substituted alkenyl group is indicated.

The term “alkynyl” refers to a hydrocarbon radical straight, branched orcyclic, containing from 2 to 10 carbon atoms and at least one carbon tocarbon triple bond. Up to three carbon-carbon triple bonds may bepresent. Thus, “C₂-C₆ alkynyl” means an alkynyl radical having from 2 to6 carbon atoms. Alkynyl groups include ethynyl, propynyl, butynyl,3-methylbutynyl and so on. The straight, branched or cyclic portion ofthe alkynyl group may contain triple bonds and may be substituted if asubstituted alkynyl group is indicated.

In certain instances, substituents may be defined with a range ofcarbons that includes zero, such as (C₀-C₆)alkylene-aryl. If aryl istaken to be phenyl, this definition would include phenyl itself as wellas —CH₂Ph, —CH₂CH₂Ph, CH(CH₃)CH₂CH(CH₃)Ph, and so on.

As used herein, “aryl” is intended to mean any stable monocyclic orbicyclic carbon ring of up to 7 atoms in each ring, wherein at least onering is aromatic. Examples of such aryl elements include phenyl,naphthyl, tetrahydronaphthyl, indanyl and biphenyl. In cases where thearyl substituent is bicyclic and one ring is non-aromatic, it isunderstood that attachment is via the aromatic ring.

The term heteroaryl, as used herein, represents a stable monocyclic orbicyclic ring of up to 7 atoms in each ring, wherein at least one ringis aromatic and contains from 1 to 4 heteroatoms selected from the groupconsisting of O, N and S. Heteroaryl groups within the scope of thisdefinition include but are not limited to: acridinyl, carbazolyl,cinnolinyl, quinoxalinyl, pyrrazolyl, indolyl, benzotriazolyl, furanyl,thienyl, benzothienyl, benzofuranyl, quinolinyl, isoquinolinyl,oxazolyl, isoxazolyl, indolyl, pyrazinyl, pyridazinyl, pyridinyl,pyrimidinyl, pyrrolyl, tetrahydroquinoline. As with the definition ofheterocycle below, “heteroaryl” is also understood to include theN-oxide derivative of any nitrogen-containing heteroaryl. In cases wherethe heteroaryl substituent is bicyclic and one ring is non-aromatic orcontains no heteroatoms, it is understood that attachment is via thearomatic ring or via the heteroatom containing ring, respectively.

The term “heterocycle” or “heterocyclyl” as used herein is intended tomean a 3- to 10-membered aromatic or nonaromatic heterocycle containingfrom 1 to 4 heteroatoms selected from the group consisting of O, N andS, and includes bicyclic groups. For the purposes of this invention, theterm “heterocyclic” is also considered to be synonymous with the terms“heterocycle” and “heterocyclyl” and is understood as also having thedefinitions set forth herein. “Heterocyclyl” therefore includes theabove mentioned heteroaryls, as well as dihydro and tetrathydro analogsthereof. Further examples of “heterocyclyl” include, but are not limitedto the following: azetidinyl, benzoimidazolyl, benzofuranyl,benzofurazanyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl,benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, imidazolyl,indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl,isoquinolyl, isothiazolyl, isoxazolyl, naphthpyridinyl, oxadiazolyl,oxazolyl, oxazoline, isoxazoline, oxetanyl, pyranyl, pyrazinyl,pyrazolyl, pyridazinyl, pyridopyridinyl, pyridazinyl, pyridyl,pyrimidyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl,tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydroisoquinolinyl,tetrazolyl, tetrazolopyridyl, thiadiazolyl, thiazolyl, thienyl,triazolyl, 1,4-dioxanyl, hexahydroazepinyl, piperazinyl, piperidinyl,pyridin-2-onyl, pyrrolidinyl, morpholinyl, thiomorpholinyl,dihydrobenzoimidazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl,dihydrobenzoxazolyl, dihydrofuranyl, dihydroimidazolyl, dihydroindolyl,dihydroisooxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl,dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl,dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl,dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl,dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl,methylenedioxybenzoyl, tetrahydrofuranyl, and tetrahydrothienyl, andN-oxides thereof. Attachment of a heterocyclyl substituent can occur viaa carbon atom or via a heteroatom.

In an embodiment, the term “heterocycle” or “heterocyclyl” as usedherein is intended to mean a 5- to 10-membered aromatic or nonaromaticheterocycle containing from 1 to 4 heteroatoms selected from the groupconsisting of O, N and S, and includes bicyclic groups. “Heterocyclyl”in this embodiment therefore includes the above mentioned heteroaryls,as well as dihydro and tetrathydro analogs thereof. Further examples of“heterocyclyl” include, but are not limited to the following:benzoimidazolyl, benzofuranyl, benzofurazanyl, benzopyrazolyl,benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl,cinnolinyl, furanyl, imidazolyl, indolinyl, indolyl, indolazinyl,indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl,isoxazolyl, naphthpyridinyl, oxadiazolyl, oxazolyl, oxazoline,isoxazoline, oxetanyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl,pyridopyridinyl, pyridazinyl, pyridyl, pyrimidyl, pyrrolyl,quinazolinyl, quinolyl, quinoxalinyl, tetrahydropyranyl,tetrahydrothiopyranyl, tetrahydroisoquinolinyl, tetrazolyl,tetrazolopyridyl, thiadiazolyl, thiazolyl, thienyl, triazolyl,azetidinyl, 1,4-dioxanyl, hexahydroazepinyl, piperazinyl, piperidinyl,pyridin-2-onyl, pyrrolidinyl, morpholinyl, thiomorpholinyl,dihydrobenzoimidazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl,dihydrobenzoxazolyl, dihydrofuranyl, dihydroimidazolyl, dihydroindolyl,dihydroisooxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl,dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl,dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl,dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl,dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl,methylenedioxybenzoyl, tetrahydrofuranyl, and tetrahydrothienyl, andN-oxides thereof. Attachment of a heterocyclyl substituent can occur viaa carbon atom or via a heteroatom.

In another embodiment, heterocycle is selected from 2-azepinone,benzimidazolyl, 2-diazapinone, imidazolyl, 2-imidazolidinone, indolyl,isoquinolinyl, morpholinyl, piperidyl, piperazinyl, pyridyl,pyrrolidinyl, 2-piperidinone, 2-pyrimidinone, 2-pyrollidinone,quinolinyl, tetrahydrofuryl, tetrahydroisoquinolinyl, and thienyl.

As appreciated by those of skill in the art, “halo” or “halogen” as usedherein is intended to include chloro, fluoro, bromo and iodo.

The alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl andheterocyclyl substituents may be substituted or unsubstituted, unlessspecifically defined otherwise. For example, a (C₁-C₆)alkyl may besubstituted with one, two or three substituents selected from OH, oxo,halogen, alkoxy, dialkylamino, or heterocyclyl, such as morpholinyl,piperidinyl, and so on. In this case, if one substituent is oxo and theother is OH, the following are included in the definition:—C═O)CH₂CH(OH)CH₃, —(C═O)OH, —CH₂(OH)CH₂CH(O), and so on.

The moiety formed when, in the definition of two R⁸s or two R⁹s on thesame carbon atom are combined to form —(CH₂)_(u)— is illustrated by thefollowing:

In addition, such cyclic moieties may optionally include one or twoheteroatom(s). Examples of such heteroatom-containing cyclic moietiesinclude, but are not limited to:

In certain instances, R¹⁰ and R¹¹ are defined such that they can betaken together with the nitrogen to which they are attached to form amonocyclic or bicyclic heterocycle with 5-7 members in each ring andoptionally containing, in addition to the nitrogen, one or twoadditional heteroatoms selected from N, O and S, said heterocycleoptionally substituted with one or more substituents selected from R⁸.Examples of the heterocycles that can thus be formed include, but arenot limited to the following, keeping in mind that the heterocycle isoptionally substituted with one or more (and in another embodiment, one,two or three) substituents chosen from R⁸:

In an embodiment of the compound of the Formula I, the dashed linerepresents a double bond.

In an embodiment of the compounds of Formula I, R¹ is selected fromhalogen, aryl, heterocyclyl and NR¹⁰R¹¹; said aryl and heterocyclylgroup optionally substituted with one to five substituents, eachsubstituent independently selected from R⁸; R⁸ independently is:

1) (C═O)_(a)O_(b)C₁-C₁₀ alkyl, 2) (C═O)_(a)O_(b)aryl, 3)C₂-C₁₀ alkenyl,4) C₂-C₁₀ alkynyl, 5) (C═O)_(a)O_(b) heterocyclyl, 6) CO₂H, 7) halo, 8)CN, 9) OH, 10) O_(b)C₁-C₆ perfluoroalkyl, 11) O_(a)(C═O)_(b)NR¹⁰R¹¹, 12)S(O)_(m)R^(a), 13) S(O)₂NR¹⁰R¹¹, 14) OS(═O)R^(a), 15) oxo, 16) CHO, 17)(N═O)R¹⁰R¹¹, 18) (C═O)_(a)O_(b)C₃-C₈ cycloalkyl, or 19) O_(b)SiR^(a) ₃,

said alkyl, aryl, alkenyl, alkynyl, heterocyclyl, and cycloalkyloptionally substituted with one, two or three substituents selected fromR⁹; and

R^(7a) and R^(7b) are each hydrogen.

In an embodiment of the compounds of Formula I, R¹ is selected from Cl,aryl, heterocyclyl, and NR¹⁰R¹¹; said aryl and heterocyclyl groupoptionally substituted with one to five substituents, each substituentindependently selected from R⁸. In a further embodiment of the compoundsof Formula I, R¹ is selected from aryl, heterocyclyl, and NR¹⁰R¹¹; saidaryl and heterocyclyl group optionally substituted with one to fivesubstituents, each substituent independently selected from R⁸. Inanother embodiment of the Formulae I and II, R¹ is selected from aryland heterocyclyl; said aryl and heterocyclyl group optionallysubstituted with one to five substituents, each substituentindependently selected from R⁸.

In an embodiment of the compound of the Formula I, R² and R³ arecombined to form ═O.

In an embodiment of the compound of the Formula I, R⁴ and R⁶ are eachindependently hydrogen, halogen, C₁₋₆alkyl, OH, —O—C₁₋₆alkyl,—O—C(═O)C₁₋₆ alkyl, —O-aryl, S(O)_(m)R^(a) and NR¹⁰R¹¹, each alkyl andaryl optionally substituted with one to five substituents, eachsubstituent independently selected from R⁸.

In an embodiment of the compound of the Formula I, R⁵ is selected fromC₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, OH, —O—C₁₋₆alkyl, —O—C(═O)C₁₋₆alkyl, —O-aryl, S(O)_(m)R^(a), —C(═O)NR¹⁰R¹¹, —NHS(O)₂NR¹⁰R¹¹ andNR¹⁰R¹¹, each alkyl, alkenyl, alkynyl and aryl optionally substitutedwith one to five substituents, each substituent independently selectedfrom R⁸.

In an embodiment of the compound of the Formula I, R⁵ is selected fromC₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, OH, —O—C₁₋₆alkyl, —O—C(═O)C₁₋₆alkyl, —O-aryl, S(O)_(m)R^(a), —C(═O)NR¹⁰R¹¹, —NHS(O)₂NR¹⁰R¹¹ andNR¹⁰R¹¹, each alkyl, alkenyl, alkynyl and aryl optionally substitutedwith one to five substituents, each substituent independently selectedfrom R⁸.

In an embodiment of the compounds of the Formula I, if R⁵ is hydrogen,then R⁴, R⁶ and R⁷ are not independently selected from hydrogen andhalogen.

In an embodiment of the Formula I, R⁷ is hydrogen.

In an embodiment, R⁶ is selected from: (C═O)_(a)O_(b)(C₁-C₁₀)alkyl,O_(b)(C₁-C₃)perfluoroalkyl, oxo, OH, halo,(C═O)_(a)O_(b)(C₀-C₆)alkylene-aryl,(C═O)_(a)O_(b)(C₀-C₆)alkylene-heterocyclyl, and S(O)_(m)R^(a); saidalkyl, aryl, and heterocyclyl is optionally substituted with one or twosubstituents selected from R⁷.

Included in the instant invention is the free form of compounds ofFormula I, as well as the pharmaceutically acceptable salts andstereoisomers thereof. Some of the specific compounds exemplified hereinare the protonated salts of amine compounds. The term “free form” refersto the amine compounds in non-salt form. The encompassedpharmaceutically acceptable salts not only include the salts exemplifiedfor the specific compounds described herein, but also all the typicalpharmaceutically acceptable salts of the free form of compounds ofFormula I. The free form of the specific salt compounds described may beisolated using techniques known in the art. For example, the free formmay be regenerated by treating the salt with a suitable dilute aqueousbase solution such as dilute aqueous NaOH, potassium carbonate, ammoniaand sodium bicarbonate. The free forms may differ from their respectivesalt forms somewhat in certain physical properties, such as solubilityin polar solvents, but the acid and base salts are otherwisepharmaceutically equivalent to their respective free forms for purposesof the invention.

The pharmaceutically acceptable salts of the instant compounds can besynthesized from the compounds of this invention which contain a basicor acidic moiety by conventional chemical methods. Generally, the saltsof the basic compounds are prepared either by ion exchangechromatography or by reacting the free base with stoichiometric amountsor with an excess of the desired salt-forming inorganic or organic acidin a suitable solvent or various combinations of solvents. Similarly,the salts of the acidic compounds are formed by reactions with theappropriate inorganic or organic base.

Thus, pharmaceutically acceptable salts of the compounds of thisinvention include the conventional non-toxic salts of the compounds ofthis invention as formed by reacting a basic instant compound with aninorganic or organic acid. For example, conventional non-toxic saltsinclude those derived from inorganic acids such as hydrochloric,hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like, aswell as salts prepared from organic acids such as acetic, propionic,succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic,pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic,salicylic, sulfanilic, 2-acetoxy-benzoic, fumaric, toluenesulfonic,methanesulfonic, ethane disulfonic, oxalic, isethionic, trifluoroaceticand the like.

When the compound of the present invention is acidic, suitable“pharmaceutically acceptable salts” refers to salts prepared formpharmaceutically acceptable non-toxic bases including inorganic basesand organic bases. Salts derived from inorganic bases include aluminum,ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganicsalts, manganous, potassium, sodium, zinc and the like. Particularlypreferred are the ammonium, calcium, magnesium, potassium and sodiumsalts. Salts derived from pharmaceutically acceptable organic non-toxicbases include salts of primary, secondary and tertiary amines,substituted amines including naturally occurring substituted amines,cyclic amines and basic ion exchange resins, such as arginine, betainecaffeine, choline, N,N¹-dibenzylethylenediamine, diethylamin,2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine,ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine,glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperidine, polyamine resins,procaine, purines, theobromine, triethylamine, trimethylaminetripropylamine, tromethamine and the like. When the compound of thepresent invention is acidic, the term “free form” refers to the compoundin its non-salt form, such that the acidic functionality is stillprotonated.

The preparation of the pharmaceutically acceptable salts described aboveand other typical pharmaceutically acceptable salts is more fullydescribed by Berg et al., “Pharmaceutical Salts,” J. Pharm. Sci.,1977:66:1-19.

It will also be noted that the compounds of the present invention maypotentially be internal salts or zwitterions, since under physiologicalconditions a deprotonated acidic moiety in the compound, such as acarboxyl group, may be anionic, and this electronic charge might then bebalanced off internally against the cationic charge of a protonated oralkylated basic moiety, such as a quaternary nitrogen atom. An isolatedcompound having internally balance charges, and thus not associated witha intermolecular counterion, may also be considered the “free form” of acompound.

Certain abbreviations, used in the Schemes and Examples, are definedbelow:

APCI Atmospheric pressure chemical ionization

DCM dichloromethane

DMF Dimethylformamide

DMSO Dimethyl sulfoxide

EtOAc Ethyl acetate

LCMS Liquid chromatographic mass spectrometry

MPLC Medium pressure liquid chromatography

NBS N-bromosuccinamide

TFA Trifluoroacetic acid

TFAA Trifluoroacetic anhydride

The compounds of this invention may be prepared by employing reactionsas shown in the following schemes, in addition to other standardmanipulations that are known in the literature or exemplified in theexperimental procedures. The illustrative schemes below, therefore, arenot limited by the compounds listed or by any particular substituentsemployed for illustrative purposes. Substituent numbering as shown inthe schemes does not necessarily correlate to that used in the claimsand often, for clarity, a single substituent is shown attached to thecompound where multiple substituents are allowed under the definitionsof Formula I hereinabove.

Schemes

As shown in Scheme A, reaction of a suitably substituted2-methylnicotinate A-1 with strong base followed by reaction with asuitably substituted bromobenzaldehyde provides the olefin intermediateA-2. Subequent poplyphiosphonic acid mediated cyclization provides theintermediate/compound of the invention A-3.

Scheme B illustrates the use of intermediate A-3 in the preparation ofinstant compounds having a variety of amine and sulfide substituents.

Scheme C illustrates the incorporation of R¹ by a Suzuki coupling of anappropriately substituted boronic acid or boronic ester with thechloride of the fused pyridyl ring of the instant compounds.

Scheme D illustrates an alternative series of reactions to the instantcompounds having substituted amine substituents on the phenyl ring.

The carbonyl moiety on the cycloheptenone ring of the instant compoundmay also be converted to a variety of substituents as shown in Scheme E.Thus hydride reduction provides the alcohol E-2, which can itselfundergo alkylation or acylation to provide E-4 and E-3 respectively.Compound E-1 can also undergo a Clemmensen reduction to provide thehydrocarbon analog E-5. The carbonyl of E-1 may also be converted to thehydroximine of E-6 and the amine of E-7 as shown.

Preparation of the instant compounds wherein R⁵ is a functionalizedmethyl is illustrated in Scheme F. Thus the ester F-1 is reduced toprovide the diol F-2, which is selectively protected and then oxidizedto provide the instant compound F-4. Deprotection provides the alcoholF-5 which may then be converted to a variety of other functional groupsby techniques well known in the art.

Scheme G illustrates an alternative procedure for forming the tricyclicring system of the instant compounds. Thus a suitably substitutednicotinoyl chloride G-1 is converted to intermediate G-2, which reactswith a suitably substituted boronic acid to provide the benzaldehydeG-3. Intermediate G-3 can then undergo base mediated cyclization toprovide the instant compound G4.

Preparation of a hydroxyl bearing alkyl sidechain for substituent R⁵ isillustrated in Scheme H starting with the vinyl substituent.

Scheme I illustrates the preparation of suitably substituted amidemoieties for substituent R¹.

Utilities

The compounds of the invention are useful to bind to and/or modulate theactivity of a tyrosine kinase, in particular, a receptor tyrosinekinase. In an embodiment, the receptor tyrosine kinase is a member ofthe MET subfamily. In a further embodiment, the MET is human MET,although the activity of receptor tyrosine kinases from other organismsmay also be modulated by the compounds of the present invention. In thiscontext, modulate means either increasing or decreasing kinase activityof MET. In an embodiment, the compounds of the instant invention inhibitthe kinase activity of MET.

The compounds of the invention find use in a variety of applications. Aswill be appreciated by those skilled in the art, the kinase activity ofMET may be modulated in a variety of ways; that is, one can affect thephosphorylation/activation of MET either by modulating the initialphosphorylation of the protein or by modulating the autophosphorylationof the other active sites of the protein. Alternatively, the kinaseactivity of MET may be modulated by affecting the binding of a substrateof MET phosphorylation.

The compounds of the invention are used to treat or prevent cellularproliferation diseases. Disease states which can be treated by themethods and compositions provided herein include, but are not limitedto, cancer (further discussed below), autoimmune disease, arthritis,graft rejection, inflammatory bowel disease, proliferation induced aftermedical procedures, including, but not limited to, surgery, angioplasty,and the like. It is appreciated that in some cases the cells may not bein a hyper- or hypoproliferation state (abnormal state) and stillrequire treatment. Thus, in one embodiment, the invention hereinincludes application to cells or individuals which are afflicted or mayeventually become afflicted with any one of these disorders or states.

The compounds, compositions and methods provided herein are particularlydeemed useful for the treatment and prevention of cancer including solidtumors such as skin, breast, brain, cervical carcinomas, testicularcarcinomas, etc. In an embodiment, the instant compounds are useful fortreating cancer. In particular, cancers that may be treated by thecompounds, compositions and methods of the invention include, but arenot limited to: Cardiac: sarcoma (angiosarcoma, fibrosarcoma,rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma andteratoma; Lung: bronchogenic carcinoma (squamous cell, undifferentiatedsmall cell, undifferentiated large cell, adenocarcinoma), alveolar(bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma,chondromatous hamartoma, mesothelioma; Gastrointestinal: esophagus(squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma),stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductaladenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors,vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors,Karposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma,fibroma), large bowel (adenocarcinoma, tubular adenoma, villous adenoma,hamartoma, leiomyoma); Genitourinary tract: kidney (adenocarcinoma,Wilm's tumor [nephroblastoma], lymphoma, leukemia,), bladder and urethra(squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma),prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma,embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma,interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors,lipoma); Liver: hepatoma (hepatocellular carcinoma), cholangiocarcinoma,hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Bone:osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibroushistiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma(reticulum cell sarcoma), multiple myeloma, malignant giant cell tumorchordoma, osteochronfroma (osteocartilaginous exostoses), benignchondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma andgiant cell tumors; Nervous system: skull (osteoma, hemangioma,granuloma, xanthoma, osteitis deformans), meninges (meningioma,meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma,glioma, ependymoma, germinoma [pinealoma], glioblastoma multiform,oligodendroglioma, schwannoma, retinoblastoma, congenital tumors),spinal cord (neurofibroma, meningioma, glioma, sarcoma); Gynecological:uterus (endometrial carcinoma), cervix (cervical carcinoma, pre-tumorcervical dysplasia), ovaries (ovarian carcinoma [serouscystadenocarcinoma, mucinous cystadenocarcinoma, unclassifiedcarcinoma], granulosa-thecal cell tumors, Sertoli-Leydig cell tumors,dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma,intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma),vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma(embryonal rhabdomyosarcoma), fallopian tubes (carcinoma); Hematologic:blood (myeloid leukemia [acute and chronic], acute lymphoblasticleukemia, chronic lymphocytic leukemia, myeloproliferative diseases,multiple myeloma, myelodysplastic syndrome), Hodgkin's disease,non-Hodgkin's lymphoma [malignant lymphoma]; Skin: malignant melanoma,basal cell carcinoma, squamous cell carcinoma, Karposi's sarcoma, molesdysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis;and Adrenal glands: neuroblastoma. Thus, the term “cancerous cell” asprovided herein, includes a cell afflicted by any one of theabove-identified conditions. In an embodiment of the invention, cancersthat may be treated by the compounds, compositions and methods of theinvention include, in addition to the cancers listed above: Lung:bronchogenic carcinoma (non-small cell lung); Gastrointestinal: rectal,colorectal and colon; Genitourinary tract: kidney (papillary renal cellcarcinoma); and Skin: head and neck squamous cell carcinoma.

In another embodiment, the compounds of the instant invention are usefulfor treating or preventing cancer selected from: head and neck squamouscell carcinomas, histiocytic lymphoma, lung adenocarcinoma, small celllung cancer, non-small cell lung cancer, pancreatic cancer, papillaryrenal cell carcinoma, liver cancer, gastric cancer, colon cancer,multiple myeloma, glioblastomas and breast carcinoma. In yet anotherembodiment, the compounds of the instant invention are useful fortreating or preventing cancer selected from: histiocytic lymphoma, lungadenocarcinoma, small cell lung cancer, pancreatic cancer, liver cancer,gastric cancer, colon cancer, multiple myeloma, glioblastomas and breastcarcinoma. In still another embodiment, the compounds of the instantinvention are useful for treating cancer selected from: histiocyticlymphoma, lung adenocarcinoma, small cell lung cancers, pancreaticcancer, liver cancer, gastric cancer, colon cancer, multiple myeloma,glioblastomas and breast carcinoma.

In another embodiment, the compounds of the instant invention are usefulfor the prevention or modulation of the metastases of cancer cells andcancer. In particular, the compounds of the instant invention are usefulto prevent or modulate the metastases of ovarian cancer, childhoodhepatocellular carcinoma, metastatic head and neck squamous cellcarcinomas, gastric cancers, breast cancer, colorectal cancer, cervicalcancer, lung cancer, nasopharyngeal cancer, pancreatic cancer,glioblastoma and sarcomas.

The compounds of this invention may be administered to mammals,preferably humans, either alone or in combination with pharmaceuticallyacceptable carriers, excipients or diluents, in a pharmaceuticalcomposition, according to standard pharmaceutical practice. Thecompounds can be administered orally or parenterally, including theintravenous, intramuscular, intraperitoneal, subcutaneous, rectal andtopical routes of administration.

The pharmaceutical compositions containing the active ingredient may bein a form suitable for oral use, for example, as tablets, troches,lozenges, aqueous or oily suspensions, dispersible powders or granules,emulsions, hard or soft capsules, or syrups or elixirs. Compositionsintended for oral use may be prepared according to any method known tothe art for the manufacture of pharmaceutical compositions and suchcompositions may contain one or more agents selected from the groupconsisting of sweetening agents, flavoring agents, coloring agents andpreserving agents in order to provide pharmaceutically elegant andpalatable preparations. Tablets contain the active ingredient inadmixture with non-toxic pharmaceutically acceptable excipients whichare suitable for the manufacture of tablets. These excipients may be forexample, inert diluents, such as calcium carbonate, sodium carbonate,lactose, calcium phosphate or sodium phosphate; granulating anddisintegrating agents, for example, microcrystalline cellulose, sodiumcrosscarmellose, corn starch, or alginic acid; binding agents, forexample starch, gelatin, polyvinyl-pyrrolidone or acacia, andlubricating agents, for example, magnesium stearate, stearic acid ortalc. The tablets may be uncoated or they may be coated by knowntechniques to mask the unpleasant taste of the drug or delaydisintegration and absorption in the gastrointestinal tract and therebyprovide a sustained action over a longer period. For example, a watersoluble taste masking material such as hydroxypropyl-methylcellulose orhydroxypropylcellulose, or a time delay material such as ethylcellulose, cellulose acetate butyrate may be employed.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with watersoluble carrier such as polyethyleneglycol or an oil medium, for examplepeanut oil, liquid paraffin, or olive oil.

Aqueous suspensions contain the active material in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose,sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example lecithin, or condensation products of an alkylene oxide withfatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose, saccharin or aspartame.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and flavoring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of ananti-oxidant such as butylated hydroxyanisol or alpha-tocopherol.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring and coloringagents, may also be present. These compositions may be preserved by theaddition of an anti-oxidant such as ascorbic acid.

The pharmaceutical compositions of the invention may also be in the formof an oil-in-water emulsions. The oily phase may be a vegetable oil, forexample olive oil or arachis oil, or a mineral oil, for example liquidparaffin or mixtures of these. Suitable emulsifying agents may benaturally occurring phosphatides, for example soy bean lecithin, andesters or partial esters derived from fatty acids and hexitolanhydrides, for example sorbitan monooleate, and condensation productsof the said partial esters with ethylene oxide, for examplepolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening, flavoring agents, preservatives and antioxidants.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol or sucrose. Such formulations mayalso contain a demulcent, a preservative, flavoring and coloring agentsand antioxidant.

The pharmaceutical compositions may be in the form of a sterileinjectable aqueous solutions. Among the acceptable vehicles and solventsthat may be employed are water, Ringer's solution and isotonic sodiumchloride solution.

The sterile injectable preparation may also be a sterile injectableoil-in-water microemulsion where the active ingredient is dissolved inthe oily phase. For example, the active ingredient may be firstdissolved in a mixture of soybean oil and lecithin. The oil solutionthen introduced into a water and glycerol mixture and processed to forma microemulation.

The injectable solutions or microemulsions may be introduced into apatient's blood stream by local bolus injection. Alternatively, it maybe advantageous to administer the solution or microemulsion in such away as to maintain a constant circulating concentration of the instantcompound. In order to maintain such a constant concentration, acontinuous intravenous delivery device may be utilized. An example ofsuch a device is the Deltec CADD-PLUS™ model 5400 intravenous pump.

The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleagenous suspension for intramuscular andsubcutaneous administration. This suspension may be formulated accordingto the known art using those suitable dispersing or wetting agents andsuspending agents which have been mentioned above. The sterileinjectable preparation may also be a sterile injectable solution orsuspension in a non-toxic parenterally acceptable diluent or solvent,for example as a solution in 1,3-butane diol. In addition, sterile,fixed oils are conventionally employed as a solvent or suspendingmedium. For this purpose any bland fixed oil may be employed includingsynthetic mono- or diglycerides. In addition, fatty acids such as oleicacid find use in the preparation of injectables.

Compounds of Formula I may also be administered in the form ofsuppositories for rectal administration of the drug. These compositionscan be prepared by mixing the drug with a suitable non-irritatingexcipient which is solid at ordinary temperatures but liquid at therectal temperature and will therefore melt in the rectum to release thedrug. Such materials include cocoa butter, glycerinated gelatin,hydrogenated vegetable oils, mixtures of polyethylene glycols of variousmolecular weights and fatty acid esters of polyethylene glycol.

For topical use, creams, ointments, jellies, solutions or suspensions,etc., containing the compound of Formula I are employed. (For purposesof this application, topical application shall include mouth washes andgargles.)

The compounds for the present invention can be administered inintranasal form via topical use of suitable intranasal vehicles anddelivery devices, or via transdermal routes, using those forms oftransdermal skin patches well known to those of ordinary skill in theart. To be administered in the form of a transdermal delivery system,the dosage administration will, of course, be continuous rather thanintermittent throughout the dosage regimen. Compounds of the presentinvention may also be delivered as a suppository employing bases such ascocoa butter, glycerinated gelatin, hydrogenated vegetable oils,mixtures of polyethylene glycols of various molecular weights and fattyacid esters of polyethylene glycol.

The dosage regimen utilizing the compounds of the instant invention canbe selected in accordance with a variety of factors including type,species, age, weight, sex and the type of cancer being treated; theseverity (i.e., stage) of the cancer to be treated; the route ofadministration; the renal and hepatic function of the patient; and theparticular compound or salt thereof employed. An ordinarily skilledphysician or veterinarian can readily determine and prescribe theeffective amount of the drug required to treat, for example, to prevent,inhibit (fully or partially) or arrest the progress of the disease.

In one exemplary application, a suitable amount of compound isadministered to a mammal undergoing treatment for cancer. Administrationoccurs in an amount between about 0.1 mg/kg of body weight to about 60mg/kg of body weight per day, preferably of between 0.5 mg/kg of bodyweight to about 40 mg/kg of body weight per day.

In a further example, compounds of the instant invention can beadministered in a total daily dose of up to 1000 mg. Compounds of theinstant invention can be administered once daily (QD), or divided intomultiple daily doses such as twice daily (BID), and three times daily(TID). Compounds of the instant invention can be administered at a totaldaily dosage of up to 1000 mg, e.g., 200 mg, 300 mg, 400 mg, 600 mg, 800mg or 1000 mg, which can be administered in one daily dose or can bedivided into multiple daily doses as described above.

In addition, the administration can be continuous, i.e., every day, orintermittently. The terms “intermittent” or “intermittently” as usedherein means stopping and starting at either regular or irregularintervals. For example, intermittent administration of a compound of theinstant invention may be administration one to six days per week or itmay mean administration in cycles (e.g. daily administration for two toeight consecutive weeks, then a rest period with no administration forup to one week) or it may mean administration on alternate days.

In addition, the compounds of the instant invention may be administeredaccording to any of the schedules described above, consecutively for afew weeks, followed by a rest period. For example, the compounds of theinstant invention may be administered according to any one of theschedules described above from two to eight weeks, followed by a restperiod of one week, or twice daily at a dose of 100-500 mg for three tofive days a week. In another particular embodiment, the compounds of theinstant invention may be administered three times daily for twoconsecutive weeks, followed by one week of rest.

The instant compounds are also useful in combination with knowntherapeutic agents and anti-cancer agents. For example, instantcompounds are useful in combination with known anti-cancer agents.Combinations of the presently disclosed compounds with other anti-canceror chemotherapeutic agents are within the scope of the invention.Examples of such agents can be found in Cancer Principles and Practiceof Oncology by V. T. Devita and S. Hellman (editors), 6^(th) edition(Feb. 15, 2001), Lippincott Williams & Wilkins Publishers. A person ofordinary skill in the art would be able to discern which combinations ofagents would be useful based on the particular characteristics of thedrugs and the cancer involved. Such anti-cancer agents include, but arenot limited to, the following: estrogen receptor modulators, androgenreceptor modulators, retinoid receptor modulators, cytotoxic/cytostaticagents, antiproliferative agents, prenyl-protein transferase inhibitors,HMG-CoA reductase inhibitors and other angiogenesis inhibitors,inhibitors of cell proliferation and survival signaling, apoptosisinducing agents and agents that interfere with cell cycle checkpoints.The instant compounds are particularly useful when co-administered withradiation therapy.

In an embodiment, the instant compounds are also useful in combinationwith known anti-cancer agents including the following: estrogen receptormodulators, androgen receptor modulators, retinoid receptor modulators,cytotoxic agents, antiproliferative agents, prenyl-protein transferaseinhibitors, HMG-CoA reductase inhibitors, HIV protease inhibitors,reverse transcriptase inhibitors, and other angiogenesis inhibitors.

“Estrogen receptor modulators” refers to compounds that interfere withor inhibit the binding of estrogen to the receptor, regardless ofmechanism. Examples of estrogen receptor modulators include, but are notlimited to, tamoxifen, raloxifene, idoxifene, LY353381, LY117081,toremifene, fulvestrant,4-[7-(2,2-dimethyl-1-oxopropoxy-4-methyl-2-[4-[2-(1-piperidinyl)ethoxy]phenyl]-2H-1-benzopyran-3-yl]-phenyl-2,2-dimethylpropanoate,4,4′-dihydroxybenzophenone-2,4-dinitrophenyl-hydrazone, and SH646.

“Androgen receptor modulators” refers to compounds which interfere orinhibit the binding of androgens to the receptor, regardless ofmechanism. Examples of androgen receptor modulators include finasterideand other 5α-reductase inhibitors, nilutamide, flutamide, bicalutamide,liarozole, and abiraterone acetate.

“Retinoid receptor modulators” refers to compounds which interfere orinhibit the binding of retinoids to the receptor, regardless ofmechanism. Examples of such retinoid receptor modulators includebexarotene, tretinoin, 13-cis-retinoic acid, 9-cis-retinoic acid,α-difluoromethylornithine, ILX23-7553,trans-N-(4′-hydroxyphenyl)retinamide, and N-4-carboxyphenyl retinamide.

“Cytotoxic/cytostatic agents” refer to compounds which cause cell deathor inhibit cell proliferation primarily by interfering directly with thecell's functioning or inhibit or interfere with cell mytosis, includingalkylating agents, tumor necrosis factors, intercalators, hypoxiaactivatable compounds, microtubule inhibitors/microtubule-stabilizingagents, inhibitors of mitotic kinesins, inhibitors of histonedeacetylase, inhibitors of kinases involved in mitotic progression,antimetabolites; biological response modifiers; hormonal/anti-hormonaltherapeutic agents, haematopoietic growth factors, monoclonal antibodytargeted therapeutic agents, topoisomerase inhibitors, proteasomeinhibitors and ubiquitin ligase inhibitors.

Examples of cytotoxic agents include, but are not limited to, sertenef,cachectin, ifosfamide, tasonermin, lonidamine, carboplatin, altretamine,prednimustine, dibromodulcitol, ranimustine, fotemustine, nedaplatin,oxaliplatin, temozolomide, heptaplatin, estramustine, improsulfantosilate, trofosfamide, nimustine, dibrospidium chloride, pumitepa,lobaplatin, satraplatin, profiromycin, cisplatin, irofulven,dexifosfamide, cis-aminedichloro(2-methyl-pyridine)platinum,benzylguanine, glufosfamide, GPX100, (trans, trans,trans)-bis-mu-(hexane-1,6-diamine)-mu-[diamine-platinum(II)]bis[diamine(chloro)platinum(II)]tetrachloride, diarizidinylspermine, arsenic trioxide,1-(11-dodecylamino-10-hydroxyundecyl)-3,7-dimethylxanthine, zorubicin,idarubicin, daunorubicin, bisantrene, mitoxantrone, pirarubicin,pinafide, valrubicin, amrubicin, antineoplaston,3′-deamino-3′-morpholino-13-deoxo-10-hydroxycarminomycin, annamycin,galarubicin, elinafide, MEN10755, and4-demethoxy-3-deamino-3-aziridinyl-4-methylsulphonyl-daunorubicin (seeWO 00/50032).

An example of a hypoxia activatable compound is tirapazamine.

Examples of proteasome inhibitors include but are not limited tolactacystin and bortezomib.

Examples of microtubule inhibitors/microtubule-stabilising agentsinclude paclitaxel, vindesine sulfate,3′,4′-didehydro-4′-deoxy-8′-norvincaleukoblastine, docetaxol, rhizoxin,dolastatin, mivobulin isethionate, auristatin, cemadotin, RPR109881,BMS184476, vinflunine, cryptophycin,2,3,4,5,6-pentafluoro-N-(3-fluoro-4-methoxyphenyl)benzene sulfonamide,anhydrovinblastine,N,N-dimethyl-L-valyl-L-valyl-N-methyl-L-valyl-L-prolyl-L-proline-t-butylamide,TDX258, the epothilones (see for example U.S. Pat. Nos. 6,284,781 and6,288,237) and BMS188797.

Some examples of topoisomerase inhibitors are topotecan, hycaptamine,irinotecan, rubitecan,6-ethoxypropionyl-3′,4′-O-exo-benzylidene-chartreusin,9-methoxy-N,N-dimethyl-5-nitropyrazolo[3,4,5-kl]acridine-2-(6H)propanamine,1-amino-9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4-methyl-1H,12H-benzo[de]pyrano[3′,4′:b,7]-indolizino[1,2b]quinoline-10,13(9H,15H)dione,lurtotecan, 7-[2-(N-isopropylamino)ethyl]-(20S)camptothecin, BNP1350,BNPI1100, BN80915, BN80942, etoposide phosphate, teniposide, sobuzoxane,2′-dimethylamino-2′-deoxy-etoposide, GL331,N-[2-(dimethylamino)ethyl]-9-hydroxy-5,6-dimethyl-6H-pyrido[4,3-b]carbazole-1-carboxamide,asulacrine,(5a,5aB,8aa,9b)-9-[2-[N-[2-(dimethylamino)ethyl]-N-methylamino]ethyl]-5-[4-hydro0xy-3,5-dimethoxyphenyl]-5,5a,6,8,8a,9-hexohydrofuro(3′,4′:6,7)naphtho(2,3-d)-1,3-dioxol-6-one,2,3-(methylenedioxy)-5-methyl-7-hydroxy-8-methoxybenzo[c]-phenanthridinium,6,9-bis[(2-aminoethyl)amino]benzo[g]isoguinoline-5,10-dione,5-(3-aminopropylamino)-7,10-dihydroxy-2-(2-hydroxyethylaminomethyl)-6H-pyrazolo[4,5,1-de]acridin-6-one,N-[1-[2(diethylamino)ethylamino]-7-methoxy-9-oxo-9H-thioxanthen-4-ylmethyl]formamide,N-(2-(dimethylamino)ethyl)acridine-4-carboxamide,6-[[2-(dimethylamino)ethyl]amino]-3-hydroxy-7H-indeno[2,1-c]quinolin-7-one,and dimesna.

Examples of inhibitors of mitotic kinesins, and in particular the humanmitotic kinesin KSP, are described in PCT Publications WO 01/30768, WO01/98278, WO 03/050,064, WO 03/050,122, WO 03/049,527, WO 03/049,679, WO03/049,678, WO04/039774, WO03/079973, WO03/099211, WO03/105855,WO03/106417, WO04/037171, WO04/058148, WO04/058700, WO04/126699,WO05/018638, WO05/019206, WO05/019205, WO05/018547, WO05/017190,US2005/0176776. In an embodiment inhibitors of mitotic kinesins include,but are not limited to inhibitors of KSP, inhibitors of MKLP1,inhibitors of CENP-E, inhibitors of MCAK, inhibitors of Kif14,inhibitors of Mphosph1 and inhibitors of Rab6-KIFL.

Examples of “histone deacetylase inhibitors” include, but are notlimited to, SAHA, TSA, oxamflatin, PXD101, MG98, valproic acid andscriptaid. Further reference to other histone deacetylase inhibitors maybe found in the following manuscript; Miller, T. A. et al. J. Med. Chem.46(24):5097-5116 (2003).

“Inhibitors of kinases involved in mitotic progression” include, but arenot limited to, inhibitors of aurora kinase, inhibitors of Polo-likekinases (PLK) (in particular inhibitors of PLK-1), inhibitors of bub-1and inhibitors of bub-R1.

“Antiproliferative agents” includes antisense RNA and DNAoligonucleotides such as G3139, ODN698, RVASKRAS, GEM231, and INX3001,and antimetabolites such as enocitabine, carmofur, tegafur, pentostatin,doxifluridine, trimetrexate, fludarabine, capecitabine, galocitabine,cytarabine ocfosfate, fosteabine sodium hydrate, raltitrexed,paltitrexid, emitefur, tiazofurin, decitabine, nolatrexed, pemetrexed,nelzarabine, 2′-deoxy-2′-methylidenecytidine,2′-fluoromethylene-2′-deoxycytidine,N-[5-(2,3-dihydro-benzofuryl)sulfonyl]-N′-(3,4-dichlorophenyl)urea,N6-[4-deoxy-4-[N2-[2(E),4(E)-tetradecadienoyl]glycylamino]-L-glycero-B-L-manno-heptopyranosyl]adenine,aplidine, ecteinascidin, troxacitabine,4-[2-amino-4-oxo-4,6,7,8-tetrahydro-3H-pyrimidino[5,4-b][1,4]thiazin-6-yl-(S)-ethyl]-2,5-thienoyl-L-glutamicacid, aminopterin, 5-flurouracil, alanosine,11-acetyl-8-(carbamoyloxymethyl)-4-formyl-6-methoxy-14-oxa-1,11-diazatetracyclo(7.4.1.0.0)-tetradeca-2,4,6-trien-9-ylacetic acid ester, swainsonine, lometrexol, dexrazoxane, methioninase,2′-cyano-2′-deoxy-N-4-palmitoyl-1-B-D-arabino furanosyl cytosine and3-aminopyridine-2-carboxaldehyde thiosemicarbazone.

Examples of monoclonal antibody targeted therapeutic agents includethose therapeutic agents which have cytotoxic agents or radioisotopesattached to a cancer cell specific or target cell specific monoclonalantibody. Examples include Bexxar.

“HMG-CoA reductase inhibitors” refers to inhibitors of3-hydroxy-3-methylglutaryl-CoA reductase. Examples of HMG-CoA reductaseinhibitors that may be used include but are not limited to lovastatin(MEVACOR®; see U.S. Pat. Nos. 4,231,938, 4,294,926 and 4,319,039),simvastatin (ZOCOR®; see U.S. Pat. Nos. 4,444,784, 4,820,850 and4,916,239), pravastatin (PRAVACHOL®; see U.S. Pat. Nos. 4,346,227,4,537,859, 4,410,629, 5,030,447 and 5,180,589), fluvastatin (LESCOL®;see U.S. Pat. Nos. 5,354,772, 4,911,165, 4,929,437, 5,189,164,5,118,853, 5,290,946 and 5,356,896) and atorvastatin (LIPITOR®; see U.S.Pat. Nos. 5,273,995, 4,681,893, 5,489,691 and 5,342,952). The structuralformulas of these and additional HMG-CoA reductase inhibitors that maybe used in the instant methods are described at page 87 of M. Yalpani,“Cholesterol Lowering Drugs”, Chemistry & Industry, pp. 85-89 (5 Feb.1996) and U.S. Pat. Nos. 4,782,084 and 4,885,314. The term HMG-CoAreductase inhibitor as used herein includes all pharmaceuticallyacceptable lactone and open-acid forms (i.e., where the lactone ring isopened to form the free acid) as well as salt and ester forms ofcompounds which have HMG-CoA reductase inhibitory activity, and thereforthe use of such salts, esters, open-acid and lactone forms is includedwithin the scope of this invention.

“Prenyl-protein transferase inhibitor” refers to a compound whichinhibits any one or any combination of the prenyl-protein transferaseenzymes, including farnesyl-protein transferase (FPTase),geranylgeranyl-protein transferase type I (GGPTase-I), andgeranylgeranyl-protein transferase type-II (GGPTase-II, also called RabGGPTase).

Examples of prenyl-protein transferase inhibitors can be found in thefollowing publications and patents: WO 96/30343, WO 97/18813, WO97/21701, WO 97/23478, WO 97/38665, WO 98/28980, WO 98/29119, WO95/32987, U.S. Pat. No. 5,420,245, U.S. Pat. No. 5,523,430, U.S. Pat.No. 5,532,359, U.S. Pat. No. 5,510,510, U.S. Pat. No. 5,589,485, U.S.Pat. No. 5,602,098, European Patent Publ. 0 618 221, European PatentPubl. 0 675 112, European Patent Publ. 0 604 181, European Patent Publ.0 696 593, WO 94/19357, WO 95/08542, WO 95/11917, WO 95/12612, WO95/12572, WO 95/10514, U.S. Pat. No. 5,661,152, WO 95/10515, WO95/10516, WO 95/24612, WO 95/34535, WO 95/25086, WO 96/05529, WO96/06138, WO 96/06193, WO 96/16443, WO 96/21701, WO 96/21456, WO96/22278, WO 96/24611, WO 96/24612, WO 96/05168, WO 96/05169, WO96/00736, U.S. Pat. No. 5,571,792, WO 96/17861, WO 96/33159, WO96/34850, WO 96/34851, WO 96/30017, WO 96/30018, WO 96/30362, WO96/30363, WO 96/31111, WO 96/31477, WO 96/31478, WO 96/31501, WO97/00252, WO 97/03047, WO 97/03050, WO 97/04785, WO 97/02920, WO97/17070, WO 97/23478, WO 97/26246, WO 97/30053, WO 97/44350, WO98/02436, and U.S. Pat. No. 5,532,359. For an example of the role of aprenyl-protein transferase inhibitor on angiogenesis see European J. ofCancer, Vol. 35, No. 9, pp. 1394-1401 (1999).

“Angiogenesis inhibitors” refers to compounds that inhibit the formationof new blood vessels, regardless of mechanism. Examples of angiogenesisinhibitors include, but are not limited to, tyrosine kinase inhibitors,such as inhibitors of the tyrosine kinase receptors Flt-1 (VEGFR1) andFlk-1/KDR (VEGFR2), inhibitors of epidermal-derived, fibroblast-derived,or platelet derived growth factors, MMP (matrix metalloprotease)inhibitors, integrin blockers, interferon-α, interleukin-12, pentosanpolysulfate, cyclooxygenase inhibitors, including nonsteroidalanti-inflammatories (NSAIDs) like aspirin and ibuprofen as well asselective cyclooxy-genase-2 inhibitors like celecoxib and rofecoxib(PNAS, Vol. 89, p. 7384 (1992); JNCI, Vol. 69, p. 475 (1982); Arch.Opthalmol., Vol. 108, p. 573 (1990); Anat. Rec., Vol. 238, p. 68 (1994);FEBS Letters, Vol. 372, p. 83 (1995); Clin, Orthop. Vol. 313, p. 76(1995); J. Mol. Endocrinol., Vol. 16, p. 107 (1996); Jpn. J. Pharmacol.,Vol. 75, p. 105 (1997); Cancer Res., Vol. 57, p. 1625 (1997); Cell, Vol.93, p. 705 (1998); Intl. J. Mol. Med., Vol. 2, p. 715 (1998); J. Biol.Chem., Vol. 274, p. 9116 (1999)), steroidal anti-inflammatories (such ascorticosteroids, mineralocorticoids, dexamethasone, prednisone,prednisolone, methylpred, betamethasone), carboxyamidotriazole,combretastatin A-4, squalamine, 6-O-chloroacetyl-carbonyl)-fumagillol,thalidomide, angiostatin, troponin-1, angiotensin II antagonists (seeFernandez et al., J. Lab. Clin. Med. 105:141-145 (1985)), and antibodiesto VEGF (see, Nature Biotechnology, Vol. 17, pp. 963-968 (October 1999);Kim et al., Nature, 362, 841-844 (1993); WO 00/44777; and WO 00/61186).

Other therapeutic agents that modulate or inhibit angiogenesis and mayalso be used in combination with the compounds of the instant inventioninclude agents that modulate or inhibit the coagulation and fibrinolysissystems (see review in Clin. Chem. La. Med. 38:679-692 (2000)). Examplesof such agents that modulate or inhibit the coagulation and fibrinolysispathways include, but are not limited to, heparin (see Thromb. Haemost.80:10-23 (1998)), low molecular weight heparins and carboxypeptidase Uinhibitors (also known as inhibitors of active thrombin activatablefibrinolysis inhibitor [TAFIa]) (see Thrombosis Res. 101:329-354(2001)). TAFIa inhibitors have been described in PCT Publication WO03/013,526 and U.S. Ser. No. 60/349,925 (filed Jan. 18, 2002).

“Agents that interfere with cell cycle checkpoints” refer to compoundsthat inhibit protein kinases that transduce cell cycle checkpointsignals, thereby sensitizing the cancer cell to DNA damaging agents.Such agents include inhibitors of ATR, ATM, the Chk1 and Chk2 kinasesand cdk and cdc kinase inhibitors and are specifically exemplified by7-hydroxystaurosporin, flavopiridol, CYC202 (Cyclacel) and BMS-387032.

“Agents that interfere with receptor tyrosine kinases (RTKs)” refer tocompounds that inhibit RTKs and therefore mechanisms involved inoncogenesis and tumor progression. Such agents include inhibitors ofc-Kit, Eph, PDGF, Flt3 and c-Met. Further agents include inhibitors ofRTKs as described by Bume-Jensen and Hunter, Nature, 411:355-365, 2001.

“Inhibitors of cell proliferation and survival signaling pathway” referto pharmaceutical agents that inhibit cell surface receptors and signaltransduction cascades downstream of those surface receptors. Such agentsinclude inhibitors of inhibitors of EGFR (for example gefitinib anderlotinib), inhibitors of ERB-2 (for example trastuzumab), inhibitors ofIGFR, inhibitors of cytokine receptors, inhibitors of MET, inhibitors ofP13K (for example LY294002), serine/threonine kinases (including but notlimited to inhibitors of Akt such as described in WO 02/083064, WO02/083139, WO 02/083140, US 2004-0116432, WO 02/083138, US 2004-0102360,WO 03/086404, WO 03/086279, WO 03/086394, WO 03/084473, WO 03/086403, WO2004/041162, WO 2004/096131, WO 2004/096129, WO 2004/096135, WO2004/096130, WO 2005/100356, WO 2005/100344), inhibitors of Raf kinase(for example BAY-43-9006), inhibitors of MEK (for example CI-1040 andPD-098059) and inhibitors of mTOR (for example Wyeth CCI-779). Suchagents include small molecule inhibitor compounds and antibodyantagonists.

“Apoptosis inducing agents” include activators of TNF receptor familymembers (including the TRAIL receptors).

The invention also encompasses combinations with NSAID's which areselective COX-2 inhibitors. For purposes of this specification NSAID'swhich are selective inhibitors of COX-2 are defined as those whichpossess a specificity for inhibiting COX-2 over COX-1 of at least 100fold as measured by the ratio of IC₅₀ for COX-2 over IC₅₀ for COX-1evaluated by cell or microsomal assays. Such compounds include, but arenot limited to those disclosed in U.S. Pat. No. 5,474,995, U.S. Pat. No.5,861,419, U.S. Pat. No. 6,001,843, U.S. Pat. No. 6,020,343, U.S. Pat.No. 5,409,944, U.S. Pat. No. 5,436,265, U.S. Pat. No. 5,536,752, U.S.Pat. No. 5,550,142, U.S. Pat. No. 5,604,260, U.S. Pat. No. 5,698,584,U.S. Pat. No. 5,710,140, WO 94/15932, U.S. Pat. No. 5,344,991, U.S. Pat.No. 5,134,142, U.S. Pat. No. 5,380,738, U.S. Pat. No. 5,393,790, U.S.Pat. No. 5,466,823, U.S. Pat. No. 5,633,272, and U.S. Pat. No.5,932,598, all of which are hereby incorporated by reference.

Inhibitors of COX-2 that are particularly useful in the instant methodof treatment are: 3-phenyl-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone;and5-chloro-3-(4-methylsulfonyl)-phenyl-2-(2-methyl-5-pyridinyl)pyridine;or a pharmaceutically acceptable salt thereof.

Compounds that have been described as specific inhibitors of COX-2 andare therefore useful in the present invention include, but are notlimited to: parecoxib, CELEBREX® and BEXTRA® or a pharmaceuticallyacceptable salt thereof.

Other examples of angiogenesis inhibitors include, but are not limitedto, endostatin, ukrain, ranpirnase, IM862,5-methoxy-4-[2-methyl-3-(3-methyl-2-butenyl)oxiranyl]-1-oxaspiro[2,5]oct-6-yl(chloroacetyl)carbamate,acetyldinanaline,5-amino-1-[[3,5-dichloro-4-(4-chlorobenzoyl)-phenyl]methyl]-1H-1,2,3-triazole-4-carboxamide,CM101, squalamine, combretastatin, RPI4610, NX31838, sulfatedmannopentaose phosphate,7,7-(carbonyl-bis[imino-N-methyl-4,2-pyrrolocarbonylimino[N-methyl-4,2-pyrrole]-carbonylimino]-bis-(1,3-naphthalenedisulfonate), and 3-[(2,4-dimethylpyrrol-5-yl)methylene]-2-indolinone(SU5416).

As used above, “integrin blockers” refers to compounds which selectivelyantagonize, inhibit or counteract binding of a physiological ligand tothe α_(v)β₃ integrin, to compounds which selectively antagonize, inhibitor counteract binding of a physiological ligand to the α_(v)β₅ integrin,to compounds which antagonize, inhibit or counteract binding of aphysiological ligand to both the α_(v)β₃ integrin and the α_(v)β₅integrin, and to compounds which antagonize, inhibit or counteract theactivity of the particular integrin(s) expressed on capillaryendothelial cells. The term also refers to antagonists of the α_(v)β₆,α_(v)β₈, α₁β₁, α₂β₁, α₅β₁, α₆β₁ and α₆β₄ integrins. The term also refersto antagonists of any combination of α_(v)β₃, α_(v)β₅, α_(v)β₆, α_(v)β₈,α₁β₁, α₂β₁, α₅β₁, α₆β₁ and α₆β₄ integrins.

Some specific examples of tyrosine kinase inhibitors includeN-(trifluoromethylphenyl)-5-methylisoxazol-4-carboxamide,3-[(2,4-dimethylpyrrol-5-yl)methylidenyl)indolin-2-one,17-(allylamino)-17-demethoxygeldanamycin,4-(3-chloro-4-fluorophenylamino)-7-methoxy-6-[3-(4-morpholinyl)propoxyl]quinazoline,N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine,BIBX1382,2,3,9,10,11,12-hexahydro-10-(hydroxymethyl)-10-hydroxy-9-methyl-9,12-epoxy-1H-diindolo[1,2,3-fg:3′,2′,1′-kl]pyrrolo[3,4-i][1,6]benzodiazocin-1-one,SH268, genistein, imatinib (STI571), CEP2563,4-(3-chlorophenylamino)-5,6-dimethyl-7H-pyrrolo[2,3-d]pyrimidinemethanesulfonate, 4-(3-bromo-4-hydroxyphenyl)amino-6,7-dimethoxyquinazoline,4-(4′-hydroxyphenyl)amino-6,7-dimethoxyquinazoline, SU6668, ST1571A,N-4-chlorophenyl-4-(4-pyridylmethyl) 1-phthalazinamine, and EMD121974.

Combinations with compounds other than anti-cancer compounds are alsoencompassed in the instant methods. For example, combinations of theinstantly claimed compounds with PPAR-γ (i.e., PPAR-gamma) agonists andPPAR-δ (i.e., PPAR-delta) agonists are useful in the treatment ofcertain malingnancies. PPAR-γ and PPAR-δ are the nuclear peroxisomeproliferator-activated receptors γ and δ. The expression of PPAR-γ onendothelial cells and its involvement in angiogenesis has been reportedin the literature (see J. Cardiovasc. Pharmacol. 1998; 31:909-913; J.Biol. Chem. 1999; 274:9116-9121; Invest. Ophthalmol Vis. Sci. 2000;41:2309-2317). More recently, PPAR-γ agonists have been shown to inhibitthe angiogenic response to VEGF in vitro; both troglitazone androsiglitazone maleate inhibit the development of retinalneovascularization in mice. (Arch. Ophthamol. 2001; 119:709-717).Examples of PPAR-γ agonists and PPAR-γ/α agonists include, but are notlimited to, thiazolidinediones (such as DRF2725, CS-011, troglitazone,rosiglitazone, and pioglitazone), fenofibrate, gemfibrozil, clofibrate,GW2570, SB219994, AR-H039242, JTT-501, MCC-555, GW2331, GW409544,NN2344, KRP297, NP0110, DRF4158, NN622, GI262570, PNU182716, DRF552926,2-[(5,7-dipropyl-3-trifluoromethyl-1,2-benzisoxazol-6-yl)oxy]-2-methylpropionicacid (disclosed in U.S. Ser. No. 09/782,856), and2(R)-7-(3-(2-chloro-4-(4-fluorophenoxy)phenoxy)propoxy)-2-ethylchromane-2-carboxylicacid (disclosed in U.S. Ser. Nos. 60/235,708 and 60/244,697).

Another embodiment of the instant invention is the use of the presentlydisclosed compounds in combination with gene therapy for the treatmentof cancer. For an overview of genetic strategies to treating cancer seeHall et al (Am J Hum Genet 61:785-789, 1997) and Kufe et al (CancerMedicine, 5th Ed, pp 876-889, B C Decker, Hamilton 2000). Gene therapycan be used to deliver any tumor suppressing gene. Examples of suchgenes include, but are not limited to, p53, which can be delivered viarecombinant virus-mediated gene transfer (see U.S. Pat. No. 6,069,134,for example), a uPA/uPAR antagonist (“Adenovirus-Mediated Delivery of auPA/uPAR Antagonist Suppresses Angiogenesis-Dependent Tumor Growth andDissemination in Mice,” Gene Therapy, August 1998; 5(8):1105-13), andinterferon gamma (J Immunol 2000; 164:217-222).

The compounds of the instant invention may also be administered incombination with an inhibitor of inherent multidrug resistance (MDR), inparticular MDR associated with high levels of expression of transporterproteins. Such MDR inhibitors include inhibitors of p-glycoprotein(P-gp), such as LY335979, XR9576, OC144-093, R101922, VX853 and PSC833(valspodar).

A compound of the present invention may be employed in conjunction withanti-emetic agents to treat nausea or emesis, including acute, delayed,late-phase, and anticipatory emesis, which may result from the use of acompound of the present invention, alone or with radiation therapy. Forthe prevention or treatment of emesis, a compound of the presentinvention may be used in conjunction with other anti-emetic agents,especially neurokinin-1 receptor antagonists, 5HT3 receptor antagonists,such as ondansetron, granisetron, tropisetron, and zatisetron, GABABreceptor agonists, such as baclofen, a corticosteroid such as Decadron(dexamethasone), Kenalog, Aristocort, Nasalide, Preferid, Benecorten orothers such as disclosed in U.S. Pat. Nos. 2,789,118, 2,990,401,3,048,581, 3,126,375, 3,929,768, 3,996,359, 3,928,326 and 3,749,712, anantidopaminergic, such as the phenothiazines (for exampleprochlorperazine, fluphenazine, thioridazine and mesoridazine),metoclopramide or dronabinol. In an embodiment, an anti-emesis agentselected from a neurokinin-1 receptor antagonist, a 5HT3 receptorantagonist and a corticosteroid is administered as an adjuvant for thetreatment or prevention of emesis that may result upon administration ofthe instant compounds.

Neurokinin-1 receptor antagonists of use in conjunction with thecompounds of the present invention are fully described, for example, inU.S. Pat. Nos. 5,162,339, 5,232,929, 5,242,930, 5,373,003, 5,387,595,5,459,270, 5,494,926, 5,496,833, 5,637,699, 5,719,147; European PatentPublication Nos. EP 0 360 390, 0 394 989, 0 428 434, 0429 366, 0 430771, 0 436 334, 0 443 132, 0 482 539, 0 498 069, 0 499 313, 0 512 901, 0512 902, 0 514 273, 0 514 274, 0 514 275, 0 514 276, 0 515 681, 0 517589, 0 520 555, 0 522 808, 0 528 495, 0 532 456, 0 533 280, 0 536 817, 0545 478, 0 558 156, 0 577 394, 0 585 913, 0 590 152, 0 599 538, 0 610793, 0 634 402, 0 686 629, 0 693 489, 0 694 535, 0 699 655, 0 699 674, 0707 006, 0 708 101, 0 709 375, 0 709 376, 0 714 891, 0 723 959, 0 733632 and 0 776 893; PCT International Patent Publication Nos. WO90/05525, 90/05729, 91/09844, 91/18899, 92/01688, 92/06079, 92/12151,92/15585, 92/17449, 92/20661, 92/20676, 92/21677, 92/22569, 93/00330,93/00331, 93/01159, 93/01165, 93/01169, 93/01170, 93/06099, 93/09116,93/10073, 93/14084, 93/14113, 93/18023, 93/19064, 93/21155, 93/21181,93/23380, 93/24465, 94/00440, 94/01402, 94/02461, 94/02595, 94/03429,94/03445, 94/04494, 94/04496, 94/05625, 94/07843, 94/08997, 94/10165,94/10167, 94/10168, 94/10170, 94/11368, 94/13639, 94/13663, 94/14767,94/15903, 94/19320, 94/19323, 94/20500, 94/26735, 94/26740, 94/29309,95/02595, 95/04040, 95/04042, 95/06645, 95/07886, 95/07908, 95/08549,95/11880, 95/14017, 95/15311, 95/16679, 95/17382, 95/18124, 95/18129,95/19344, 95/20575, 95/21819, 95/22525, 95/23798, 95/26338, 95/28418,95/30674, 95/30687, 95/33744, 96/05181, 96/05193, 96/05203, 96/06094,96/07649, 96/10562, 96/16939, 96/18643, 96/20197, 96/21661, 96/29304,96/29317, 96/29326, 96/29328, 96/31214, 96/32385, 96/37489, 97/01553,97/01554, 97/03066, 97/08144, 97/14671, 97/17362, 97/18206, 97/19084,97/19942 and 97/21702; and in British Patent Publication Nos. 2 266 529,2 268 931, 2 269 170, 2 269 590, 2 271 774, 2 292 144, 2 293 168, 2 293169, and 2 302 689. The preparation of such compounds is fully describedin the aforementioned patents and publications, which are incorporatedherein by reference.

In an embodiment, the neurokinin-1 receptor antagonist for use inconjunction with the compounds of the present invention is selectedfrom:2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)-phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)morpholine,or a pharmaceutically acceptable salt thereof, which is described inU.S. Pat. No. 5,719,147.

A compound of the instant invention may also be useful for treating orpreventing cancer, including bone cancer, in combination withbisphosphonates (understood to include bisphosphonates, diphosphonates,bisphosphonic acids and diphosphonic acids). Examples of bisphosphonatesinclude but are not limited to: etidronate (Didronel), parnidronate(Aredia), alendronate (Fosamax), risedronate (Actonel), zoledronate(Zometa), ibandronate (Boniva), incadronate or cimadronate, clodronate,EB-1053, minodronate, neridronate, piridronate and tiludronate includingany and all pharmaceutically acceptable salts, derivatives, hydrates andmixtures thereof.

A compound of the instant invention may also be administered with anagent useful in the treatment of anemia. Such an anemia treatment agentis, for example, a continuous eythropoiesis receptor activator (such asepoetin alfa).

A compound of the instant invention may also be administered with anagent useful in the treatment of neutropenia. Such a neutropeniatreatment agent is, for example, a hematopoietic growth factor whichregulates the production and function of neutrophils such as a humangranulocyte colony stimulating factor, (G-CSF). Examples of a G-CSFinclude filgrastim.

A compound of the instant invention may also be administered with animmunologic-enhancing drug, such as levamisole, isoprinosine andZadaxin.

A compound of the instant invention may also be useful for treating orpreventing cancer, including bone cancer, in combination withbisphosphonates (understood to include bisphosphonates, diphosphonates,bisphosphonic acids and diphosphonic acids). Examples of bisphosphonatesinclude but are not limited to: etidronate (Didronel), pamidronate(Aredia), alendronate (Fosamax), risedronate (Actonel), zoledronate(Zometa), ibandronate (Boniva), incadronate or cimadronate, clodronate,EB-1053, minodronate, neridronate, piridronate and tiludronate includingany and all pharmaceutically acceptable salts, derivatives, hydrates andmixtures thereof.

A compound of the instant invention may also be useful for treating orpreventing breast cancer in combination with aromatase inhibitors.Examples of aromatase inhibitors include but are not limited to:anastrozole, letrozole and exemestane.

A compound of the instant invention may also be useful for treating orpreventing cancer in combination with siRNA therapeutics.

The compounds of the instant invention may also be administered incombination with γ-secretase inhibitors and/or inhibitors of NOTCHsignaling. Such inhibitors include compounds described in WO 01/90084,WO 02/30912, WO 01/70677, WO 03/013506, WO 02/36555, WO 03/093252, WO03/093264, WO 03/093251, WO 03/093253, WO 2004/039800, WO 2004/039370,WO 2005/030731, WO 2005/014553, U.S. Ser. No. 10/957,251, WO2004/089911, WO 02/081435, WO 02/081433, WO 03/018543, WO 2004/031137,WO 2004/031139, WO 2004/031138, WO 2004/101538, WO 2004/101539 and WO02/47671 (including LY-450139).

A compound of the instant invention may also be useful for treating orpreventing cancer in combination with PARP inhibitors.

A compound of the instant invention may also be useful for treatingcancer in combination with the following therapeutic agents: abarelix(Plenaxis depot®); aldesleukin (Prokine®); Aldesleukin (Proleukin®);Alemtuzumabb (Campath®); alitretinoin (Panretin®); allopurinol(Zyloprim®); altretamine (Hexalen®); amifostine (Ethyol®); anastrozole(Arimidex®); arsenic trioxide (Trisenox®); asparaginase (Elspar®);azacitidine (Vidaza®); bevacuzimab (Avastin®); bexarotene capsules(Targretin®); bexarotene gel (Targretin®); bleomycin (Blenoxane®);bortezomib (Velcade®); busulfan intravenous (Busulfex®); busulfan oral(Myleran®); calusterone (Methosarb®); capecitabine (Xeloda®);carboplatin (Paraplatin®); carmustine (BCNU®, BiCNU®); carmustine(Gliadel®); carmustine with Polifeprosan 20 Implant (Gliadel Wafer®);celecoxib (Celebrex®); cetuximab (Erbitux®); chlorambucil (Leukeran®);cisplatin (Platinol®); cladribine (Leustatin®, 2-CdA®); clofarabine(Clolar®); cyclophosphamide (Cytoxan®, Neosar®); cyclophosphamide(Cytoxan Injection®); cyclophosphamide (Cytoxan Tablet®); cytarabine(Cytosar-U®); cytarabine liposomal (DepoCyt®); dacarbazine (DTIC-Dome®);dactinomycin, actinomycin D (Cosmegen®); Darbepoetin alfa (Aranesp®);daunorubicin liposomal (DanuoXome®); daunorubicin, daunomycin(Daunorubicin®); daunorubicin, daunomycin (Cerubidine®); Denileukindiftitox (Ontak®); dexrazoxane (Zinecard®); docetaxel (Taxotere®);doxorubicin (Adriamycin PFS®); doxorubicin (Adriamycin®, Rubex®);doxorubicin (Adriamycin PFS Injection®); doxorubicin liposomal (Doxil®);DROMOSTANOLONE PROPIONATE (DROMOSTANOLONE®); DROMOSTANOLONE PROPIONATE(MASTERONE INJECTION®); Elliott's B Solution (Elliott's B Solution®);epirubicin (Ellence®); Epoetin alfa (epogen®); erlotinib (Tarceva®);estramustine (Emcyt®); etoposide phosphate (Etopophos®); etoposide,VP-16 (Vepesid®); exemestane (Aromasin®); Filgrastim (Neupogen®);floxuridine (intraarterial) (FUDR®); fludarabine (Fludara®);fluorouracil, 5-FU (Adrucil®); fulvestrant (Faslodex®); gefitinib(Iressa®); gemcitabine (Gemzar®); gemtuzumab ozogamicin (Mylotarg®);goserelin acetate (Zoladex Implant®); goserelin acetate (Zoladex®);histrelin acetate (Histrelin implant®); hydroxyurea (Hydrea®);Ibritumomab Tiuxetan (Zevalin®); idarubicin (Idamycin®); ifosfamide(IFEX®); imatinib mesylate (Gleevec®); interferon alfa 2a (Roferon A®);Interferon alfa-2b (Intron A®); irinotecan (Camptosar®); lenalidomide(Revlimid®); letrozole (Femara®); leucovorin (Wellcovorin®,Leucovorin®); Leuprolide Acetate (Eligard®); levamisole (Ergamisol®);lomustine, CCNU (CeeBU®); meclorethamine, nitrogen mustard (Mustargen®);megestrol acetate (Megace®); melphalan, L-PAM (Alkeran®);mercaptopurine, 6-MP (Purinethol®); mesna (Mesnex®); mesna (Mesnextabs®); methotrexate (Methotrexate®); methoxsalen (Uvadex®); mitomycin C(Mutamycin®); mitotane (Lysodren®); mitoxantrone (Novantrone®);nandrolone phenpropionate (Durabolin-50); nelarabine (Arranon®);Nofetumomab (Verluma®); Oprelvekin (Neumega®); oxaliplatin (Eloxatin®);paclitaxel (Paxene®); paclitaxel (Taxol®); paclitaxel protein-boundparticles (Abraxane®); palifermin (Kepivance®); pamidronate (Aredia®);pegademase (Adagen (Pegademase Bovine)®); pegaspargase (Oncaspar®);Pegfilgrastim (Neulasta®); pemetrexed disodium (Alimta®); pentostatin(Nipent®); pipobroman (Vercyte®); plicamycin, mithramycin (Mithracin®);porfimer sodium (Photofrin®); procarbazine (Matulane®); quinacrine(Atabrine®); Rasburicase (Elitek®); Rituximab (Rituxan®); sargramostim(Leukine®); Sargramostim (Prokine®); sorafenib (Nexavar®); streptozocin(Zanosar®); sunitinib maleate (Sutent®); talc (Sclerosol®); tamoxifen(Nolvadex®); temozolomide (Temodar®); teniposide, VM-26 (Vumon®);testolactone (Teslac®); thioguanine, 6-TG (Thioguanine®); thiotepa(Thioplex®); topotecan (Hycamtin®); toremifene (Fareston®); Tositumomab(Bexxar®); Tositumomab/I-131 tositumomab (Bexxar®); Trastuzumab(Herceptin®); tretinoin, ATRA (Vesanoid®); Uracil Mustard (UracilMustard Capsules®); valrubicin (Valstar®); vinblastine (Velban®);vincristine (Oncovin®); vinorelbine (Navelbine®); and zoledronate(Zometa®).

Thus, the scope of the instant invention encompasses the use of theinstantly claimed compounds in combination with a second compoundselected from: an estrogen receptor modulator, an androgen receptormodulator, retinoid receptor modulator, a cytotoxic/cytostatic agent, anantiproliferative agent, a prenyl-protein transferase inhibitor, anHMG-CoA reductase inhibitor, an HIV protease inhibitor, a reversetranscriptase inhibitor, an angiogenesis inhibitor, a PPAR-γ agonist, aPPAR-δ agonist, an inhibitor of inherent multidrug resistance, ananti-emetic agent, an agent useful in the treatment of anemia, an agentuseful in the treatment of neutropenia, an immunologic-enhancing drug,an inhibitor of cell proliferation and survival signaling, an apoptosisinducing agent, a bisphosphonate, an aromatase inhibitor, an siRNAtherapeutic γ-secretase inhibitors, agents that interfere with receptortyrosine kinases (RTKs), an agent that interferes with a cell cyclecheckpoint and any of the therapeutic agents listed above.

Any one or more of the specific dosages and dosage schedules of thecompounds of the instant invention, may also be applicable to any one ormore of the therapeutic agents to be used in the combination treatment(hereinafter refered to as the “second therapeutic agent”).

Moreover, the specific dosage and dosage schedule of this secondtherapeutic agent can further vary, and the optimal dose, dosingschedule and route of administration will be determined based upon thespecific second therapeutic agent that is being used.

Of course, the route of administration of the compounds of the instantinvention is independent of the route of administration of the secondtherapeutic agent. In an embodiment, the administration for a compoundof the instant invention is oral administration. In another embodiment,the administration for a compound of the instant invention isintravenous administration. Thus, in accordance with these embodiments,a compound of the instant invention is administered orally orintravenously, and the second therapeutic agent can be administeredorally, parenterally, intraperitoneally, intravenously, intraarterially,transdermally, sublingually, intramuscularly, rectally, transbuccally,intranasally, liposomally, via inhalation, vaginally, intraoccularly,via local delivery by catheter or stent, subcutaneously,intraadiposally, intraarticularly, intrathecally, or in a slow releasedosage form.

In addition, a compound of the instant invention and second therapeuticagent may be administered by the same mode of administration, i.e. bothagents administered e.g. orally, by IV. However, it is also within thescope of the present invention to administer a compound of the instantinvention by one mode of administration, e.g. oral, and to administerthe second therapeutic agent by another mode of administration, e.g. IVor any other ones of the administration modes described hereinabove.

The first treatment procedure, administration of a compound of theinstant invention, can take place prior to the second treatmentprocedure, i.e., the second therapeutic agent, after the treatment withthe second therapeutic agent, at the same time as the treatment with thesecond therapeutic agent, or a combination thereof. For example, a totaltreatment period can be decided for a compound of the instant invention.The second therapeutic agent can be administered prior to onset oftreatment with a compound of the instant invention or followingtreatment with a compound of the instant invention. In addition,anti-cancer treatment can be administered during the period ofadministration of a compound of the instant invention but does not needto occur over the entire treatment period of a compound of the instantinvention.

The term “administration” and variants thereof (e.g., “administering” acompound) in reference to a compound of the invention means introducingthe compound or a prodrug of the compound into the system of the animalin need of treatment. When a compound of the invention or prodrugthereof is provided in combination with one or more other active agents(e.g., a cytotoxic agent, etc.), “administration” and its variants areeach understood to include concurrent and sequential introduction of thecompound or prodrug thereof and other agents.

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombination of the specified ingredients in the specified amounts.

The term “therapeutically effective amount” as used herein means thatamount of active compound or pharmaceutical agent that elicits thebiological or medicinal response in a tissue, system, animal or humanthat is being sought by a researcher, veterinarian, medical doctor orother clinician.

The term “treating cancer” or “treatment of cancer” refers toadministration to a mammal afflicted with a cancerous condition andrefers to an effect that alleviates the cancerous condition by killingthe cancerous cells, but also to an effect that results in theinhibition of growth and/or metastasis of the cancer.

In an embodiment, the angiogenesis inhibitor to be used as the secondcompound is selected from a tyrosine kinase inhibitor, an inhibitor ofepidermal-derived growth factor, an inhibitor of fibroblast-derivedgrowth factor, an inhibitor of platelet derived growth factor, an MMP(matrix metalloprotease) inhibitor, an integrin blocker, interferon-α,interleukin-12, pentosan polysulfate, a cyclooxygenase inhibitor,carboxyamidotriazole, combretastatin A-4, squalamine,6-O-chloroacetyl-carbonyl)-fumagillol, thalidomide, angiostatin,troponin-1, or an antibody to VEGF. In an embodiment, the estrogenreceptor modulator is tamoxifen or raloxifene.

Also included in the scope of the claims is a method of treating cancerthat comprises administering a therapeutically effective amount of acompound of Formula I in combination with radiation therapy and/or incombination with a compound selected from: an estrogen receptormodulator, an androgen receptor modulator, retinoid receptor modulator,a cytotoxic/cytostatic agent, an antiproliferative agent, aprenyl-protein transferase inhibitor, an HMG-CoA reductase inhibitor, anHIV protease inhibitor, a reverse transcriptase inhibitor, anangiogenesis inhibitor, a PPAR-γ agonist, a PPAR-δ agonist, an inhibitorof inherent multidrug resistance, an anti-emetic agent, an agent usefulin the treatment of anemia, an agent useful in the treatment ofneutropenia, an immunologic-enhancing drug, an, inhibitor of cellproliferation and survival signaling, an apoptosis inducing agent, abisphosphonate, an aromatase inhibitor, an siRNA therapeutic and anagent that interferes with a cell cycle checkpoint.

And yet another embodiment of the invention is a method of treatingcancer that comprises administering a therapeutically effective amountof a compound of Formula I in combination with paclitaxel ortrastuzumab.

The invention further encompasses a method of treating or preventingcancer that comprises administering a therapeutically effective amountof a compound of Formula I in combination with a COX-2 inhibitor.

The instant invention also includes a pharmaceutical composition usefulfor treating or preventing cancer that comprises a therapeuticallyeffective amount of a compound of Formula I and a compound selectedfrom: an estrogen receptor modulator, an androgen receptor modulator, aretinoid receptor modulator, a cytotoxic/cytostatic agent, anantiproliferative agent, a prenyl-protein transferase inhibitor, anHMG-CoA reductase inhibitor, an HIV protease inhibitor, a reversetranscriptase inhibitor, an angiogenesis inhibitor, a PPAR-γ agonist, aPPAR-β agonist; an inhibitor of cell proliferation and survivalsignaling, a bisphosphonate, an aromatase inhibitor, an siRNAtherapeutic and an agent that interferes with a cell cycle checkpoint.

Further included within the scope of the invention is a method oftreating or preventing a disease in which angiogenesis is implicated,which is comprised of administering to a mammal in need of suchtreatment a therapeutically effective amount of a compound of thepresent invention. Other inhibitors of MET may also be administered forthis method of treatment. Ocular neovascular diseases, which may resultin certain forms of blindness, are examples of conditions where much ofthe resulting tissue damage can be attributed to aberrant infiltrationof blood vessels in the eye. The undesirable infiltration can betriggered by ischemic retinopathy, such as that resulting from diabeticretinopathy, retinopathy of prematurity, retinal vein occlusions, etc.,or by degenerative diseases, such as the choroidal neovascularizationobserved in age-related macular degeneration. Inhibiting the growth ofblood vessels by administration of the present compounds would thereforeprevent the infiltration of blood vessels and prevent or treat diseaseswhere angiogenesis is implicated, such as ocular diseases like retinalvascularization, diabetic retinopathy, age-related macular degeneration,and the like.

Routes of systemic administration of the compounds of the presentinvention described above may be utilized in the treatment of suchocular neovascular diseases. Other routes of ocular administration mayalso be employed, such as topical, periocular, intravitreal and thelike. Intravitreal implants coated with a drug:polymer matrix may alsobe employed.

Ophthalmic pharmaceutical compositions that are adapted for topicaladministration to the eye may be in the form of solutions, suspensions,ointments, creams or as a solid insert. Ophthalmic formulations of thiscompound may contain from 0.01 ppm to 1% and especially 0.1 ppm to 1% ofmedicament. For a single dose, from between 0.01 to 5000 ng, preferably0.1 to 500 ng, and especially 1 to 100 ng of the compound can be appliedto the human eye. Formulations useful for intravitreal administrationare similar to saline solutions described previously for intravenousadministration.

These and other aspects of the invention will be apparent from theteachings contained herein.

Assays

The compounds of the instant invention described in the Examples weretested by the assays described below and were found to have METinhibitory activity. Other assays are known in the literature and couldbe readily performed by those of skill in the art (see, for example,U.S. Patent Application Publications US 2005/0075340 A1, Apr. 7, 2005,pages 18-19; and PCT Publication WO 2005/028475, Mar. 31, 2005, pages236-248).

I. In Vitro Kinase Assays

Recombinant GST-tagged cytosolic domains of human c-Met and otherreceptor tyrosine kinases including mouse c-Met, human Ron, KDR, IGFR,EGFR, FGFR, Mer, TrkA and Tie2 are used to determine whether thecompounds of the instant invention modulate the enzymatic activities ofthese kinases.

Soluble recombinant GST-tagged cytosolic domains of c-Met and otherreceptor tyrosine kinases are expressed in a baculovirus system(Pharmingen) according to a protocol recommended by the manufacturer.The c-DNA encoding each cytosolic domain is subcloned into a baculovirusexpression vector (pGcGHLT-A, B or C, Pharmingen) containing an in frame6× histidine tag and a GST tag. The resulting plasmid construct andBaculoGold baculovirus DNA (Pharmingen) are used to co-transfect Sf9 orSf21 insect cells. After confirming expression of GST-tagged kinasefusion, a high titer recombinant baculovirus stock is produced,expression conditions are optimized, and a scaled up expression of ratKDR-GST fusion is performed. The fusion kinase is then purified from theinsect cell lysate by affinity chromatography using glutathione agarose(Pharmingen). The purified protein is dialyzed against 50% glycerol, 2mM DTT, 50 mM Tris-HCl (pH 7.4) and stored at −20° C. The proteinconcentrations of the fusion proteins are determined using CoomassiePlus Protein Assay (Pierce) with BSA as standard.

The kinase activities of c-Met and other kinases are measured using amodified version of the homogeneous time-resolved tyrosine kinase assaydescribed by Park et al. (1999, Anal. Biochem. 269:94-104).

The procedure for determining the potency of a compound to inhibit c-Metkinase comprises the following steps:

-   -   1. Prepare 3-fold serial diluted compound solutions in 100%        dimethyl sulfoxide (DMSO) at 20× of the desired final        concentrations in a 96 well plate.    -   2. Prepare a master reaction mix containing 6.67 mM MgCl₂, 133.3        mM NaCl, 66.7 mM Tris-HCl (pH 7.4), 0.13 mg/ml BSA, 2.67 mM        dithiothreitol, 0.27 nM recombinant c-Met and 666.7 nM        biotinylated synthetic peptide substrate        (biotin-ahx-EQEDEPEGDYFEWLE-CONH₂) (SEQ.ID.NO.: 1).    -   3. In a black assay plate, add 2.5 μl of compound solution (or        DMSO) and 37.5 μl of master reaction mix per well. Initiate the        kinase reaction by adding 10 μL of 0.25 mM MgATP per well. Allow        the reactions to proceed for 80 min at room temperature. The        final conditions for the reaction are 0.2 nM c-Met, 0.5 μM        substrate, 50 μM MgATP, 5 mM MgCl₂, 100 mM NaCl, 2 mM DTT, 0.1        mg/ml BSA, 50 mM Tris (pH 7.4) and 5% DMSO.    -   4. Stop the kinase reaction with 50 μl of Stop/Detection buffer        containing 10 mM EDTA, 25 mM HEPES, 0.1% TRITON X-100, 0.126        μg/ml Eu-chelate labeled anti-phosphotyrosine antibody PY20        (cat. # AD0067, PerkinElmer) and 45 μg/ml        Streptavidin-allophycocyanin conjugate (cat. # PJ25S, Prozyme).    -   5. Read HTRF signals on a Victor reader (PerkinElmer) in HTRF        mode after 60 min.    -   6. IC₅₀ is determined by fitting the observed relationship        between compound concentration and HTRF signal with a        4-parameter logistic equation.        Essentially the same procedure was used to determine the potency        of compounds to inhibit mouse c-Met, human Ron, KDR, IGFR, EGFR,        FGFR, Mer, TrkA and Tie2 except that the concentration of enzyme        varied in individual assays (0.2 nM mouse c-Met; 2.5 nM Ron, 8        nM KDR; 0.24 nM IGFR; 0.24 nM EGFR; 0.14 nM FGFR; 16 nM Mer; 8        nM TrkA; 8 nM Tie2).

The compounds 3 and 5 to 235 in the Examples were tested in the aboveassay and found to have an IC₅₀≦50 μM.

II. Cell Based-c-Met Autophosphorylation Assay

A sandwich ELISA assay is used to assess MET autophosphorylation inMKN45 gastric cancer cells, in which MET is constitutively activated.Briefly a monolayer of cells was pre-treated with compounds or thevehicle and then lysed. The MET in a cell lysate was captured by ananti-MET antibody immobilized on a plastic surface. A genericanti-phosphotyrosine antibody or one of several specificanti-phospho-MET antibodies is then allowed to bind captured MET and isdetected using HRP-conjugated secondary antibody.

The procedure for determining the potency of a compound to inhibit METautophosphorylation in MKN45 cells comprises the following steps:

Day 1

-   -   1. Coat a 96-well ELISA plate overnight at 4° C. with 100        μl/well of 1 μg/ml capture antibody solution (Af276, R&D).    -   2. Seed a separate 96-well culture plate with MKN45 cells at        90,000 cells/well in 0.1 ml of growth media (RPMI 1640, 10% FBS,        100 ug/mL Pen-Strep, 100 ug/mL L-glutamine, and 10 mM HEPES) and        culture overnight at 37° C./5% CO₂ to 80-90% confluence.        Day 2    -   1. Wash the ELISA plate 4× with 200 μl/well of wash buffer        (TBST+0.25% BSA). Incubate the ELISA plate with 200 μl/well of        blocking buffer (TBST+1.5% BSA) for 3-5 hrs at RT.    -   2. Prepare a half-long dilution series of of 200× compound in        DMSO. Dilute the series to 10× with assay media (RPMI 1640, 10%        FBS, and 10 mM HEPES).    -   3. Add 10× compound solutions (11 μl/well) to the culture plate        containing MKN45 cells. Incubate the plate at 37° C./5% CO₂ for        60 min.    -   4. Lyse the cells with 100 μl/well of lysis buffer (30 mM Tris,        pH 7.5, 5 mM EDTA, 50 mM NaCl, 30 mM sodium pyrophosphate, 50 mM        NaF, 0.5 mM Na₃VO₄, 0.25 mM potassium        bisperoxo(1,10-phenanthroline)-oxovanadate, 0.5% NP40, 1% Triton        X-100, 10% glycerol, and a protease inhibitor cocktail) at 4° C.        for 90 min.    -   5. Remove blocking buffer from the ELISA plate, wash the plate        4× with 200 μl/well of wash buffer. Transfer 90 μl/well of MKN45        cell lysate from the culture plate to the ELISA plate. Incubate        sealed assay plate at 4° C. with gentle shaking overnight.        Day 3    -   1. Wash the ELISA plates 4 times with 200 μl/well wash buffer.    -   2. Incubate with 100 μl/well primary detection antibody (1 μg/ml        in TBST+1% BSA) for 1.5 hours at ambient temperature. The        following primary antibodies have been used: 4G10 from UpState,        anti-pMet(1349) and anti-pMet(1369), both from Biosource.    -   3. Wash the ELISA plates 4 times with wash buffer. Add 100        μl/well of secondary antibody (1:1000 anti-mouse IgG-HRP diluted        in TBST+1% BSA for 4G10, or 1:1000 anti-rabbit IgG-HRP for        anti-pMet(1349) and anti-pMet(1365)). Incubate at room        temperature with gentle mixing for 1.5 hours. Wash 4× with 200        ul/well wash buffer.    -   4. Add 100 μl/well of Quanta Blu reagent (Pierce) and incubate        at room temperature for 8 minutes. Read fluorescence (Excitation        wavelength: 314 nm, emission wavelength: 425 nm) on a Spectramax        Gemini EM plate reader (Molecular Devices).    -   5. IC₅₀ is calculated by fitting the relationship between        compound concentration and fluorescence signal with a        4-parameter logistic equation.        III. MKN45 Cell Proliferation/Viability Assay

MKN45 human gastric cancer cells are known to over-expressconstitutively activated c-met. siRNA-mediated partial knock down ofc-Met was found to induce pronounced growth inhibition and apoptosis inMKN45 cells, suggesting a vital role of c-Met in this cell line. Theassay described here measures the effect of c-Met inhibitors onproliferation/viability of MKN45 cells. The procedure for determiningthe potency of a compound to inhibit MKN45 proliferation/viabilitycomprises the following steps.

On day 1, plate MKN45 cells at 3000 cells/95 μl medium (RPMI/10% FCS,100 mM HEPES, penicillin and streptomycin) per well in a 96 well plate.Maintain the plate in an incubator at 37° C./5% CO₂. Prepare 3-foldserial diluted compound solutions at 1000× of desired finalconcentrations: in DMSO.

On day 2, prepare 50× compound solutions by diluting the 1000× compoundsolutions with the medium. Add 5 μl 20× compound solution per well tothe MKN45 cell culture described above. Return the plate to theincubator.

On day 5, add 50 μl lysis buffer (ViaLight Reagents Kit, Catalog No.LT07-221, Cambrex): per well. Lyse the cells at room temperature for 15minutes. Then add 50 μl detection reagent (ViaLight Reagents Kit) andincubate for 3 minutes. The plate is read on a TOPCOUNT (PerkinElmer) inluminescence mode. IC₅₀ is calculated by fitting the relationshipbetween compound concentration and luminescence signal with a4-parameter logistic equation.

IV. HGF-Induced Cell Migration Assay

The HGF-induced migration of HPAF pancreatic cancer cells was assessedusing BD Falcon Fluoroblock 96-Multiwell Insert plates (Cat # 351164, BDDiscovery Labware). The plate consists of wells each of which ispartitioned by a micro-porous membrane into the top and bottom chambers.Pancreatic cancer cells are plated on the top side of the membrane andmigrate to the underside of the membrane in response to chemo-attractantadded to the lower chamber. The cells on the under side of the membraneare labeled with a fluorescent dye and detected by a fluorescence platereader. The procedure for determining the potency of a compound toinhibit cell migration comprises the following steps.

-   -   1. Prepare test compound solutions of 1000× final concentrations        in 100% DMSO    -   2. Dilute the above solutions 50× with DMEM/10% FCS to obtain        compound solutions 20× of the final concentrations.    -   3. Fill each lower chamber of a Fluoroblock 96-Muntiwell Insert        plate with 180 μl DMEM/10% FCS, and plate 8,000 HPAF pancreatic        cancer cells in 50 ul DMEM/10% FCS in each upper chamber.    -   4. 1-2 hours after plating, add 2.5 μl and 10 μl of a 20×        compound solution to the upper and the lower chamber        respectively. Incubate the plate at 37° C. for 60 min, and then        add concentrated HGF to lower chamber to a final HGF        concentration of 15 ng/ml. The insert plates are incubated        overnight for 20 hours.    -   5. An aliquot of a concentrated Calcein dye (Molecular Probes)        is added to each lower chamber to give 5 μg/ml final dye        concentration and the cells are labeled for 1 hour. Wash each        lower chamber with 200 μl DMEM/10% FCS    -   6. Read fluorescence on a Victor reader (PerkinElmer) in bottom        read mode (Excitation wave length: 485 nm, emission wavelength:        535 nm).    -   7. IC₅₀ is calculated by fitting the relationship between        compound concentration and fluorescence signal with a        4-parameter logistic equation.

EXAMPLES

Examples provided are intended to assist in a further understanding ofthe invention. Particular materials employed, species and conditions areintended to be illustrative of the invention and not limiting of thereasonable scope thereof.

Example 1

Step 1: 2-[(E/Z)-2-(4-bromophenyl)vinyl]-3-carboxy-5-chloropyridiniumchloride

Potassium tert-butoxide (1M solution in THF, 60 mL, 60 mmol) was addedto a solution of 4-bromobenzaldehyde (5.6 g, 30 mmol) and methyl5-chloro-2-methylnicotinate (Marcoux, J.-F.; Marcotte, F.-A.; Wu, J.;Dormer, P. G.; Davies, I. W.; Hughes, D.; Reider, P. J. J. Org. Chem.2001, 66, 4194-4199) (5.6 g, 30 mmol) in 200 mL THF at 0° C. The mixturewas allowed to warm to ambient temperature and stirred for 12 hours. Thereaction slurry was concentrated to give yellow/orange solids, then 50mL of water and 50 mL of 6N HCl were added. After stirring the resultingslurry for 30 minutes, 200 mL of EtOH was added and the slurry wasstirred for 4 hours. The slurry was filtered and dried to afford thetitle compound. ¹H NMR (600 MHz, DMSO-D₆) δ 8.76 (d, 1H); 8.22 (d, 1H);8.02 (d, 1H); 7.79 (d, 1H); 7.60-7.54 (m, 4H). LRMS (APCI) calculatedfor C₁₄H₁₀BrClNO₂ [M+H]+, 338.0; found 337.9.

Step 2: 7-bromo-3-chloro-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one(Compound 1)

2-[(E/Z)-2-(4-bromophenyl)vinyl]-3-carboxy-5-chloropyridinium chloride(11.2 g, 29.9 mmol) was added to 50 mL of polyphosphoric acid and heatedto 200° C. After 12 hours, the solution was poured into ice and 250 mLof 5N sodium hydroxide solution, then 5N sodium hydroxide solution wasadded to adjust to pH 10. The mixture was diluted in 2 L ofdichloromethane, 100 g of Celite were added and the suspension wasstirred for 15 minutes. The solids were filtered through a sinteredglass funnel and discarded. The liquid phase was poured into aseparatory funnel and the organic layer was isolated. The organic layerwas dried with magnesium sulfate, filtered, and concentrated to affordCompound 1. ¹H NMR (600 MHz, CDCl₃) δ 8.82 (d, 1H); 8.50 (d, 1H); 8.41(d, 1H); 7.80 (dd, 1H); 7.48 (d, 1H); 7.35 (d, 1H); 7.20 (d, if H). LRMS(APCI) calculated for C₁₄H₈BrClNO [M+H]+, 320.0; found 320.0.

Example 2

Step 1: S-(4-methylphenyl)2-methyl-5-phenylpyridine-3-carbothioate

To a 0° C. solution of 2-methyl-5-phenylnicotinic acid (100 mg, 0.40mmol) in CH₂Cl₂ (4 mL) was added oxalyl chloride (344 μL, 4.0 mmol). Themixture was stirred at 40° C. After 3 hours, the mixture wasconcentrated to dryness, dissolved in benzene (2×5 mL) and concentratedagain. After dissolving the crude residue in CH₂Cl₂ (2 mL) at 0° C.,pyridine (1 mL, 0.92 M in CH₂Cl₂), 4-dimethylaminopyridine (10 mg, 0.08mmol) and 4-methylthiophenol (60 mg, 0.48 mmol) were added. The mixturewas then allowed to warm to room temperature. After stirring for 2hours, the mixture was diluted with EtOAc, washed with 1N HCl, brine,dried over sodium sulfate, filtered, and concentrated. The crude residuewas purified by flash chromatography (100-80% hexanes/EtOAc gradient) toafford the title compound. LRMS (APCI) calculated for C₂₀H₁₈NOS [M+H]+,320.1; found 320.1

Step 2: 2-[(2-methyl-5-phenylpyridin-3-yl)carbonyl]benzaldehyde

S-(4-methylphenyl)2-methyl-5-phenylpyridine-3-carbothioate (100 mg, 0.31mmol), copper (I) thiophene-2-carboxylate (89.6 mg, 0.47 mmol), Pd₂dba₃CHCl₃ (26 mg, 0.025 mmol), tri-2-furylphosphine (17.3 mg, 0.074mmol) and 2-formylphenylboronic acid (51.7 mg, 0.34 mmol) were combinedin a dry flask. The flask was purged with argon and 3.0 mL of THF wereadded. Argon was bubbled through the solution for 5 minutes and thesolution was stirred and heated to 50° C. After 18 hours, the reactionmixture was diluted with EtOAc, washed with 1N HCl, brine, dried oversodium sulfate, filtered, concentrated and purified by flashchromatography (100-70% hexanes/EtOAc gradient) to afford the titlecompound. LRMS (APCI) calculated for C₂₀H₁₆NO₂ [M+H]⁺, 302.1; found302.1

Step 3: 3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one

A flask was charged with2-[(2-methyl-5-phenylpyridin-3-yl)carbonyl]benzaldehyde (6.2 mg, 0.02mmol) and MeOH (1 mL). LiHMDS (25 μl, 1.0 M in THF) was added and thevessel was heated in the Biotage Initiator series microwave for 30 min.at 100° C. The mixture was then diluted with EtOAc, washed with waterand brine, then dried over Na₂SO₄. The solution was concentrated invacuo and purified by reverse phase HPLC (0-100% CH₃CN/water with a 0.1%TFA modifier) to afford the title compound. ¹H NMR (600 MHz, CD₃OD) δ9.15 (d, 1H), 8.76 (d, 1H), 8.25 (d, 1H), 7.77 (m, 4H), 7.66 (t, 1H),7.54 (t, 2H), 7.45 (m, 2H0, 7.36 (d, 1H). LRMS (APCI) calculated forC₂₀H₁₄NO [M+H]+, 284.1; found 283.8

The following compounds were made according to Scheme 1, using theappropriately substituted 2-formylphenylboronic acids, which wereprepared according to literature methods. TABLE 1 Compound StructureName MS (M + 1) 3

6-bromo-3-phenyl-5H- benzo[4,5]cyclohepta[1,2- b]pyridin-5-one calc'd362.0 (M + H)+; found (M + H)+ 4

7-bromo-3-phenyl-5H- benzo[4,5]cyclohepta[1,2- b]pyridin-5-one calc'd362.0 (M + H)+; found 362.0 (M + H)+ 5

8-bromo-3-phenyl-5H- benzo[4,5]cyclohepta[1,2- b]pyridin-5-one calc'd362.0 (M + )+; found (M + )+ 6

9-bromo-3-phenyl-5H- benzo[4,5]cyclohepta[1,2- b]pyridin-5-one calc'd362.0 (M + H)+; found (M + H)+

Example 3

3-chloro-7-[(2,4-dimethoxybenzyl)amino]-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one

7-bromo-3-chloro-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one (3.0 g,9.40 mmol), tris(dibenzylideneacetone)dipalladium (0) (Pd₂(dba₃)) (43mg, 0.047 mmol), rac-2,2′-bis(diphenylphosphino)-1,1′-binapthyl (BINAP)(88 mg, 0.141 mmol), and sodium tert-butoxide (1.08 g, 11.3 mmol) werecombined in a dry flask through which argon was purged. The flask wascharged with 100 mL of dry dioxane, 2,4-dimethoxybenzylamine (1.41 mL,9.40 mmol) was added, and the mixture was sparged with argon for 5minutes. The reaction was heated to 100° C. and stirred under argon.After 2 h the reaction was concentrated and dissolved in 400 ml of ethylacetate and washed with 100 mL of saturated aqueous ammonium chloridesolution. The organic layer was separated, dried with magnesium sulfate,filtered, and concentrated. The resultant solids were slurried in 50 mLhot methanol, then allowed to cool to ambient temperature. The solidswere filtered and dried to afford the title compound. LRMS (APCI)calculated for C₂₃H₂₀ClN₂O₃ [M+H]+, 407.1; found 407.1.

Example 4

7-amino-3-chloro-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one

Method A:

7-bromo-3-chloro-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one (1.05 g,3.30 mmol), Pd₂(dba)₃ (8 mg, 0.00825 mmol), BINAP (15 mg, 0.0248 mmol)and benzophenone imine (0.662 mL, 3.95 mmol) were combined in a dryflask. The flask was charged with 40 mL of dry toluene, followed bysodium tert-butoxide (0.444 g, 4.62 mmol). Argon was bubbled through thesolution for 5 minutes. The reaction solution was heated to 110° C. andstirred under argon. After 2.5 hours, the reaction was concentrated, 20mL of THF and 1 mL of 6N hydrochloric acid were added and the resultingsolution was stirred. After 2 hours, the solution was poured into 300 mLof ethyl acetate, 100 mL of saturated sodium bicarbonate and 200 mL ofwater. The organic layers were separated, dried with magnesium sulfate,filtered, concentrated, and purified by flash column chromatography(0-30% ethyl acetate/hexanes gradient) to afford the title compound. ¹HNMR (600 MHz, CDCl₃) δ 8.77 (d, 1H); 8.55 (d, 1H); 7.58 (d, 1H); 7.44(d, 1H); 7.18 (d, 1H); 7.14 (d, 1H); 7.01 (dd, 1H); 4.15 (s, 2H). LRMS(APCI) calculated for C₁₄H₁₀ClN₂O [M+H]+, 257.0; found 257.1.

Method B:

3-chloro-7-[(2,4-dimethoxybenzyl)amino]-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one(1.1 g, 2.7 mmol) was dissolved in 8 mL methanol and 30 mLdichloromethane. Then 10 mL of trifluoroacetic acid was added and thesolution was stirred at ambient temperature. After 1 hour, reaction wasconcentrated, dissolved in 500 mL of ethyl acetate and washed with 200mL saturated sodium bicarbonate. The organic layer was separated, driedwith magnesium sulfate, filtered, and purified by flash columnchromatography (0-10% methanol/dichloromethane gradient) and reversephase HPLC (20-100% acetonitrile/water gradient, 0.1% trifluoroaceticacid modifier) to afford title compound. LRMS (APCI) calculated forC₁₄H₁₀ClN₂O [M+H]+, 257.0; found 257.1.

Example 5

N-(3-chloro-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)methanesulfonamide

Method A:

7-bromo-3-chloro-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one (5.00 g.15.7 mmol), methyl sulfonamide (1.49 g, 15.7 mmol), Pd₂(dba)₃ (0.714 g,0.78 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino) xanthene (XANTPHOS)(1.36 g, 2.35 mmol) and cesium carbonate (15.3 g, 47.0 mmol) were addedto a dry flask through which argon was purged. The flask was chargedwith 100 mL of dry dioxane and argon was bubbled through the solutionfor 10 minutes. The reaction mixture was heated to 95° C. and stirredunder argon. After 12 hours, the reaction mixture was concentrated anddissolved in 2000 mL ethyl acetate and 1000 mL water. The organic layerwas separated and washed with 500 mL of brine, dried with magnesiumsulfate, filtered, and concentrated. The resultant solids were dissolvedin 150 mL of a 3:1 mixture of hot dichloromethane/methanol and allowedto cool to ambient temperature with stirring. After 3 h, 150 mL ofhexanes were added and the resulting slurry was allowed to stir. After12 hours, an additional 50 mL hexanes were added. After 4 hours, thesolids were filtered and dried to afford the title compound.

Method B:

7-amino-3-chloro-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one (0.70 g,2.7 mmol), triethylamine (0.83 mL, 5.94 mmol) andmethanesulfonylchloride (0.42 mL, 5.4 mmol) were added to 40 mLdichloromethane and cooled to 0° C. The solution was stirred and allowedto warm to ambient temperature. After 1 hour, the reaction was quenchedwith saturated sodium bicarbonate solution and stirred. After 30minutes, the reaction mixture was poured into 300 mL ethyl acetate and250 mL water. The organic layer was separated, dried with magnesiumsulfate, filtered, and concentrated to afford crudeN,N-(3-chloro-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)bis-methanesulfonamide.

The crudeN,N-(3-chloro-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)bis-methanesulfonamide(1.1 g, 2.7 mmol) was dissolved in 150 mL methanol, then 5 mL of 5Nsodium hydroxide solution was added and the solution was stirred atambient temperature. After 1 hour, the reaction solution was partiallyconcentrated and dissolved in 250 mL of ethyl acetate, 150 mL water, and50 mL saturated aqueous ammonium chloride solution. The organic layerwas separated, dried with magnesium sulfate, filtered, and concentratedto afford the title compound.

¹H NMR (600 MHz, CDCl₃) δ 8.82 (d, 1H); 8.54 (d, 1H); 7.98 (d, 1H); 7.70(dd, 1H); 7.65 (d, 1H); 7.33 (d, 1H); 7.25 (d, 1H); 6.78 (s, 1H); 3.12(s, 3H). LRMS (APCI) calculated for C₁₅H₁₂ClN₂O₃S [M+H]+, 335.0; found335.1.

Example 6

6-(methylthio)-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one

6-bromo-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one (15 mg,0.04 mmol), sodium thiomethoxide (15 mg, 0.21 mmol) and copper (1)bromide (23 mg, 0.10 mmol) were combined in a dry flask. The flask waspurged with argon and 0.5 mL of N,N-dimethylformamide were added. Thesolution was stirred and heated to 140° C. After 72 h, the reactionmixture was cooled to room temperature, diluted with EtOAc and washedwith 5% HCl, brine and water. The organic layer was dried over sodiumsulfate, filtered, concentrated and purified by reverse phase HPLC(30-100% acetonitrile/water gradient, 0.1% trifluoroacetic acidmodifier) to afford the title compound. ¹H NMR (600 MHz, CD₃OD) δ 9.14(d, 1H), 8.58 (d, 1H), 7.78 (d, 2H), 7.65 (m, 2H), 7.54 (t, 2H), 7.47(m, 3H), 7.27 (d, 1H), 2.49 (s, 3H). LRMS (APCI) calculated forC₂₁H₁₆NOS [M+H]+, 330.0; found 330.1

Example 7

6-(methylsulfonyl)-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one

To a 0° C. solution of6-(methylthio)-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one (7.4mg, 0.022 mmol) in THF (0.7 mL) and MeOH (0.2 mL) was added oxone (0.3mL, 0.138 M in water). The mixture was then stirred at room temperature.After 2 hours, the reaction mixture was concentrated to dryness. Thecrude residue was diluted with EtOAc and washed with brine. The organiclayer was dried over sodium sulfate, filtered, concentrated and purifiedby reverse phase HPLC (30-100% acetonitrile/water gradient, 0.1%trifluoroacetic acid modifier) to afford the title compound. ¹H NMR (600MHz, CD₃OD) δ 9.10 (d, 1H), 8.40 (d, 1H), 8.26 (d, 1H), 8.00 (d, 1H),7.85 (t, 1H), 7.75 (d, 2H), 7.53 (t, 2H), 7.47 (m, 2H), 7.38 (d, 1H),3.52 (s, 3H). LRMS (APCI) calculated for C₂₁H₁₆NO₃S [M+H]+, 362.0; found362.1

Example 8

Methyl5-oxo-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-7-carboxylate

A test tube fitted with a Teflon lined septum was charged with compound4 (50 mg, 0.14 mmol) and Pd(PPh₃)₄ (8 mg, 0.007 mmol) then flushed withAr for 5 min. Then DMF (2 mL), MeOH (1 mL) and triethylamine (0.2 mL,1.4 mmol) were added and the solution was sparged with CO_((g)) for 10min then placed under a CO balloon and heated to 60° C. After 18 h, thesolution was concentrated in vacuo and purified by reverse phase HPLC(20-100% CH₃CN/water with a 0.1% TFA modifier) to afford the titlecompound 12. ¹H NMR (600 MHz, CDCl₃) δ 9.15 (d, 1H); 8.92 (d, 1H); 8.72(d, 1H); 8.30 (dd, 1H); 7.70-7.73 (m, 2H); 7.67 (d, 1H); 7.44-7.55 (m,4H); 7.30 (d, 1H); 3.98 (s, 3H). LRMS (APCI) calc'd for (C₂₂H₁₆NO₃)[M+H]+, 342.1; found 342.1.

Example 9

6-methyl-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one

6-bromo-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one (10 mg,0.027 mmol), trimethylboroxine (10 μL, 0.071 mmol),tetrakis(triphenylphosphine)palladium (0) (5 mg, 0.004 mmol), andpotassium carbonate (15 mg, 0.108 mmol) were combined in a dry flask.The flask was purged with argon and 0.5 mL of 10% aqueous dioxane wereadded. Argon was bubbled through the solution for 5 minutes and thesolution was stirred and heated to 100° C. After 12 hours, the reactionmixture was filtered through a pad of Celite, eluted with EtOAc, washedwith brine, dried over sodium sulfate, filtered, concentrated andpurified by reverse phase HPLC (30-100% acetonitrile/water gradient,0.1% trifluoroacetic acid modifier) to afford the title compound. ¹H NMR(600 MHz, CD₃OD) δ 9.11 (d, 1H), 8.54 (d, 1H), 7.80 (d, 2H), 7.54 (m,5H), 7.48 (m, 2H), 7.26 (d, 2H), 2.56 (s, 3H). LRMS (APCI) calculatedfor C₂₁H₁₆NO [M+H]+, 298.1; found 298.1

Example 10

3-phenyl-7-[(trimethylsilyl)ethynyl]-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one

A test tube fitted with a Teflon lined septum was charged with compound4 (100.0 mg, 0.276 mmol), PdCl₂(PPh₃)₂ (19 mg, 0.03 mmol), CuI (11 mg,0.06 mmol), and 3 mL of DMF. The mixture was sparged with Ar for 5 min,then triethylamine (0.19 mL, 1.4 mmol) and trimethylsilylacetylene (0.06mL, 0.41 mmol) were added and the mixture was heated to 50° C. for 18 h.The solution was diluted with EtOAc and washed with water and brine thendried over Na₂SO₄. The solution was concentrated in vacuo and purifiedby flash column chromatography (10-70% EtOAc/hexanes gradient) to affordthe title compound 14. ¹H NMR (600 MHz, CDCl₃) δ 8.88 (d, 1H); 8.51 (s,1H); 8.12 (d, 1H); 7.41-7.48 (m, 3H); 7.18-7.30 (m, 5H); 7.01 (d, 1H);0.00 (s, 9H). LRMS (APCI) calc'd for (C₂₅H₂₂NOSi) [M+H]+, 380.1; found380.1.

Example 11

3-phenyl-7-vinyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one

A test tube fitted with a Teflon lined septum was charged with compound4 (100.0 mg, 0.276 mmol), PdCl₂(PPh₃)₂ (10 mg, 0.014 mmol),tri-n-butylvinyltin (0.089 mL, 0.30 mmol) and 3 mL of dioxane. Themixture was sparged with Ar for 10 min, then heated to 95° C. overnight.The solution was diluted with EtOAc and washed with water and brine thendried over Na₂SO₄. The solution was concentrated in vacuo and purifiedby flash column chromatography (10-70% EtOAc/hexanes gradient) to afforda white solid. This sold was dissolved in 10 mL of 1:1:1EtOAc/dichloromethane/water mixture and 82 mg of CsF was added. After 2h, the organic layer was separated and the aqueous layer was extractedwith EtOAc and the organic layers dried over Na₂SO₄. The solution wasconcentrated in vacuo and purified by flash column chromatography(0-10-20-100% EtOAc/hexanes step gradient) to afford the title compound15. ¹H NMR (600 MHz, CDCl₃) δ 9.14 (s, 1H); 8.78 (s, 1H); 8.30 (s, 1H);7.75-7.78 (m, 1H); 7.70-7.74 (m, 2H); 7.59 (d, 1H); 7.50-7.55 (m, 2H);7.40-7.47 (m, 2H); 7.30 (d, 1H); 6.85 (dd, 1H); 5.95 (d, 1H); 5.43 (d,1H). LRMS (APCI) calc'd for (C₂₂H₁₆NO) [M+H]+, 310.1; found 310.2

Example 12

7-ethyl-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one

A flask was charged with compound 15 (20.0 mg, 0.065 mmol), 8 mg of 10%palladium on carbon, 3 mL of EtOH, 3 mL of EtOAc, and 0.5 mL of 1N HCl.The flask was fitted with a three-way stopcock with a hydrogen balloon,then evacuated and flushed with hydrogen four times. After 1 h thereaction mixture was filtered through a 0.45μ Nylon syringe filter,concentrated in vacuo and purified by reverse phase HPLC (20-100%CH₃CN/water with a 0.1% TFA modifier) to afford the title compound 16.¹H NMR (600 MHz, CDCl₃) δ 9.13 (s, 1H); 8.75 (s, 1H); 8.13 (s, 1H);7.70-7.73 (m, 2H); 7.49-7.55 (m, 4H); 7.42-7.46 (m, 1H); 7.37 (d, 1H);7.28 (d, 1H); 2.81 (q, 2H); 1.31 (t, 3H). LRMS (APCI) calc'd for(C₂₂H₁₈NO) [M+H]+, 312.1; found 312.2

Example 13

N-(5-oxo-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)acetamide

A flask was charged with compound 4 (25.0 mg, 0.069 mmol), CuI (0.6 mg,0.003 mmol) and K₂CO₃ (19 mg, 0.14 mmol) then flushed with Ar for 5 min.DMF (1 mL) was added and the mixture was sparged with Ar for 5 min thenN,N′-dimethylethylenediamine (one drop from a 22G needle) was added andthe mixture was sparged with Ar for an additional 10 min. The mixturewas heated to 80° C. for 18 h, then at 110° C. for an additional 24 h.The mixture was cooled to room temperature and filtered through a pad ofCelite, concentrated in vacuo and purified by reverse phase HPLC(20-100% CH₃CN/water with a 0.1% TFA modifier) to afford the titlecompound 17. ¹H NMR (600 MHz, CDCl₃) δ 9.09 (d, 1H); 8.71 (d, 1H); 8.24(dd, 1H); 8.05 (d, 1H); 7.64-7.67 (m, 2H); 7.56 (d, 1H); 7.42-7.48 (m,3H); 7.37-7.41 (m, 1H); 7.31 (d, 1H); 7.21 (d, 1H); 2.18 (s, 3H). LRMS(APCI) calc'd for (C₂₂H₁₆N₂O₂Na) [M+Na]+, 363.1; found 363.1.

Example 14

Step 1:(3-chloro-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)boronic acid

7-bromo-3-chloro-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one (1.00 g,3.12 mmol), Pd₂(dba)₃ (0.146 g, 0.16 mmol), tricyclohexylphosphine(0.104 g, 0.37 mmol), bis(pinacolato)diboron (0.87 g, 3.43 mmol) andpotassium acetate (0.61 g, 6.23 mmol) were mixed in a dry flask throughwhich argon was purged. The flask was charged with 40 mL of dry dioxaneand argon was bubbled through the solution for 15 minutes. The reactionwas heated to 95° C. and stirred under argon. After 6 h, the reactionmixture was poured into 500 mL of ethyl acetate and 100 mL of saturatedaqueous ammonium chloride. The organic layer was separated, dried withmagnesium sulfate, filtered, and concentrated to afford the titlecompound. LRMS (APCI) calculated for C₁₄H₁₀BClNO₃ [M+H]+, 286.0; found286.1.

Step 2: 3-chloro-7-hydroxy-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one(Compound 18)

(3-chloro-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)boronic acid(1.00 g, 3.5 mmol) was dissolved in a 0° C. solution of 25 mL of THF, 25mL of water, 0.5 mL of acetic acid and 0.5 mL of 30% (w/w) hydrogenperoxide. The solution was stirred and allowed to warm to ambienttemperature. After 6 h, the reaction mixture was partially concentratedand dissolved in 500 mL ethyl acetate. The organic layer was washed withwater (2×100 mL), dried with magnesium sulfate, filtered, andconcentrated to afford solids. The solids were dissolved in 20 mLdichloromethane and 60 mL hexanes and stirred as solids crystallizedfrom the solution. After 2 hours, the crystalline solids were filteredand dried to afford the title compound. ¹H NMR (600 MHz, DMSO-D₆) δ10.50 (s, 1H); 8.93 (s, 1H); 8.45 (s, 1H); 7.68 (d, 1H); 7.58 (d, 1H);7.39 (d, 1H); 7.23 (d, 1H); 7.12 (d, 1H). LRMS (APCI) calculated forC₁₄H₉ClNO₂ [M+H]+, 258.0; found 258.1.

Example 15

N-benzyl-N-methylsulfamide

N,N-dialkyl sulfamides were prepared according to the publishedprocedures: Winum, J-Y; Toupet, L.; Barragan, V.; Dewynter, G.; Montero,J.-L. Org. Letters 2001, 3, 2241-2243 and Casini, A.; Winum, J.-Y.;Montero, J.-L.; Scozzafava, A.; Supuran, C. Bioorganic & MedicinalChemistry Letters 2003, 13, 837-840. A flask was charged withN-tert-butoxycarbonyl-N-[4-(dimethylazaniumylidene)-1,4-dihydropyridin-1-ylsulfonyl]azanide(500 mg, 1.66 mmol) and methylbenzylamine (0.21 mL, 1.66 mmol) in 10 mLof CH₂Cl₂. After 2 h, the solution was concentrated in vacuo andpurified by flash column chromatography (5-70% EtOAc/hexanes) to afford304 mg of tert-butyl {[benzyl(methyl)amino]sulfonyl}carbamate.

tert-butyl {[benzyl(methyl)amino]sulfonyl}carbamate (257 mg, 0.856 mmol)was dissolved in 5 mL of CH₂Cl₂ and 1 mL of trifluoroacetic acid. After1 h an additional 1 mL of trifluoroacetic acid was added and thesolution was stirred for a further 2 h. The solution was neutralizedwith aqueous saturated NaHCO₃, diluted in CH₂Cl₂, washed with saturatedNaHCO₃ and brine, then dried over Na₂SO₄. The solution was concentratedin vacuo to afford the title compound A. ¹H NMR (600 MHz, CDCl₃) δ7.30-7.38 (m, 5H); 4.27-4.31 (m, 4H); 2.73 (s, 3H); LRMS (APCI) calc'dfor (C₈H₁₃N₂O₂S) [M+H]+, 201.1; found 200.8

The following compounds were made according to Scheme 3. Additionalsynthetic modifications were employed in the preparation of some of thecompounds. Compounds 28 and 29 were isolated from the reaction mixtureof Compounds 26 and 27 respectively. Compound 31 was prepared byhydrolysis of Compound 12. Compound 32 was prepared by EDCI mediatedcoupling of methylamine to Compound 31. Compound 36 was prepared by TBAFmediated desilylation of Compound 14. Compound 41 was isolated bysubjecting Compound 4 to the reaction conditions described for theformation of Compound 10. Compound 43 was prepared from Compound 3 byCu(I)Br mediated coupling with sodium methoxide in a manner similar tothat described for Compound 10. TABLE 2 Compound Structure Name MS(M + 1) 19

7-[(2,4- dimethoxybenzyl)amino]- 3-phenyl-5H- benzo[4,5]cyclohepta[1,2-b]pyridin-5-one calc'd 449.2 (M + H)+; found 449.2 (M + H)+ 20

6-amino-3-phenyl-5H- benzo[4,5]cyclohepta[1,2- b]pyridin-5-one calc'd299.1 (M + H)+; found (M + H)+ 21

7-amino-3-phenyl-5H- benzo[4,5]cyclohepta[1,2- b]pyridin-5-one calc'd299.1 (M + H)+; found 299.1 (M + H)+ 22

8-amino-3-phenyl-5H- benzo[4,5]cyclohepta[1,2- b]pyridin-5-one calc'd299.1 (M + H)+; found (M + H)+ 23

9-amino-3-phenyl-5H- benzo[4,5]cyclohepta[1,2- b]pyridin-5-one calc'd299.1 (M + H)+; found (M + H)+ 24

2-hydroxy-N-(5-oxo-3- phenyl-5H- benzo[4,5]cyclohepta[1,2- b]pyridin-7-yl)propanamide calc'd 371.1 (M + H)+; found 371.1 (M + H)+ 25

3-phenyl-7-(pyridin-2- ylamino)-5H- benzo[4,5]cyclohepta[1,2-b]pyridin-5 -one calc'd 376.1 (M + H)+; found 376.1 (M + H)+ 26

7-[(3- methoxypropyl)amino]-3- phenyl-5H- benzo[4,5]cyclohepta[1,2-b]pyridin-5-one calc'd 371.2 (M + H)+; found 371.2 (M + H)+ 27

7-[(2- methoxyethyl)amino]-3- phenyl-5H- benzo[4,5]cyclohepta[1,2-b]pyridin-5-one calc'd 357.2 (M + H)+; found 357.2 (M + H)+ 28

7-[(2- methoxypropyl)amino]-3- phenyl-5H- benzo[4,5]cyclohepta[1,2-b]pyridin-5-ol calc'd 373.2 (M + H)+; found 373.2 (M + H)+ 29

7-[(2- methoxyethyl)amino]-3- phenyl-5H- benzo[4,5]cyclohepta[1,2-b]pyridin-5-one calc'd 359.2 (M + H)+; found 359.2 (M + H)+ 30

3-phenyl-7-[(2,2,2- trifluoroethyl)amino]-5H- benzo[4,5]cyclohepta[1,2-b]pyridin-5-one calc'd 381.1 (M + H)+; found 381.1 (M + H)+ 31

5-oxo-3-phenyl-5H- benzo[4,5]cyclohepta[1,2- b]pyridine-7-carboxylicacid, isolated as the HCl salt calc'd 328.1 (M + H)+; found 328.1 (M +H)+ 32

N-methyl-5-oxo-3- phenyl-5H-benzo[4,5]- cyclohepta[1,2- b]pyridine-7-carboxamide, TFA salt calc'd 341.1 (M + H)+; found 341.1 (M + H)+ 33

7-methyl-3-phenyl-5H- benzo[4,5]cyclohepta[1,2- b]pyridin-5-one calc'd298.1 (M + H)+; found 298.1 (M + H)+ 34

8-methyl-3-phenyl-5H- benzo[4,5]cyclohepta[1,2- b]pyridin-5-one M,1calc'd 298.1 (M + H)+; found (M + H)+ 35

9-methyl-3-phenyl-5H- benzo[4,5]cyclohepta[1,2- b]pyridin-5-one calc'd298.1 (M + H)+; found (M + H)+ 36

7-ethynyl-3-phenyl-5H- benzo[4,5]cyclohepta[1,2- b]pyridin-5-one calc'd308.1 (M + H)+; found 308.1 (M + H)+ 37

3-phenyl-7-[(1E/Z)-prop- 1-en-1-yl]-5H- benzo[4,5]cyclohepta[1,2-b]pyridin-5-one calc'd 324.1 (M + H)+; found 324.2 (M + H)+ 38

3-phenyl-7-propyl-5H- benzo[4,5]cyclohepta[1,2- b]pyridin-5-one calc'd326.1 (M + H)+; found 326.2 (M + H)+ 39

7-isobutyl-3-phenyl-5H- benzo[4,5]cyclohepta[1,2- b]pyridin-5-one calc'd340.2 (M + H)+; found 340.2 (M + H)+ 40

9-(methylthio)-3-phenyl- 5H- benzo[4,5]cyclohepta[1,2- blpyridin-5-onecalc'd 330.0 (M + H)+; found (M + H)+ 41

7-(methylthio)-3-phenyl- 10,11-dihydro-5H- benzo[4,5]cyclohepta[1,2-b]pyridin-5-one calc'd 332.1 (M + H)+; found 332.1 (M + H)+ 42

9-(methylsulfonyl)-3- phenyl-5H- benzo[4,5]cyclohepta[1,2-b]pyridin-5-one calc'd 362.0 (M + H)+; found (M + H)+ 43

6-methoxy-3-phenyl-5H- benzo[4,5]cyclohepta[1,2- b]pyridin-5-one calc'd314.1 (M + H)+; found (M + H)+ 44

N-(5-oxo-3-phenyl-5H- benzo[4,5]cyclohepta[1,2- b]pyridin-7-yl)methanesulfonamide calcd 377.1 (M + H)+; found 377.1 (M + H)+ 45

N′-(3-chloro-5-oxo-5H- benzo[4,5]cyclohepta[1,2- b]pyridin-7-yl)-N,N-dimethylsulfamide calc'd 364.0 (M + H)+; found 363.7 (M + H)+ 46

N-benzyl-N′-(3-chloro-5- oxo-5H- benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)-N- methylsulfamide calc'd 440.1 (M + H)+; found 439.6(M + H)+ 47

N-(3-chloro-5-oxo-5H- benzo[4,5]cyclohepta[1,2- b]pyridin-7-yl)-1,1,1-trifluoromethanesulfonamide calc'd 389.0 (M + H)+; found 388.6 (M + H)+48

3-chloro-7-{[(3- methylpyridin-4- yl)methyl]amino}-5H-benzo[4,5]cyclohepta[1, 2-b]pyridin-5-one calc'd 362.1 (M + H)+; found362.1 (M + H)+ 49

N′-(3-chloro-5-oxo-5H- benzo[4,5]cyclohepta[1,2- b]pyridin-7-yl)-N-(isoxazol-3-ylmethyl)-N- methylsulfamide calc'd 431.1 (M + H)+; found431.0 (M + H)+ 50

N-(3-chloro-5-oxo-5H- benzo[4,5]cyclohepta[1, 2-b]pyridin-7-yl)-N′-[(1-morpholin-4- ylcyclopentyl)methyl]sulfamide calc'd 503.1 (M + H)+;found 503.2 (M + H)+ 51

3,7-bis[(pyridin-3- ylmethyl)amino]-5H- benzol[4,5]cyclohepta[1,2-b]pyridin-5-one calc'd 420.2 (M + H)+; found 420.2 (M + H)+ 52

3-chloro-7-[(pyridin-2- ylmethyl)amino]-5H- benzo[4,5]cyclohepta[1,2-b]pyridin-5-one calc'd 348.1 (M + H)+; found 348.1 (M + H)+

Example 16

N-[5-oxo-3-(3-thienyl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide

N-(3-chloro-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)methanesulfonamide(0.100 g, 0.30 mmol), 3-thienylboronic acid (0.077 g, 0.60 mmol),tetrakis(triphenylphosphine)palladium (0) (10 mg, 0.009 mmol) andpotassium carbonate (0.124 g, 0.90 mmol) were combined in a dry flask.The flask was purged with argon and 5 mL of dry dioxane was added. Argonwas bubbled through the solution for 5 minutes and the solution wasstirred and heated to 100° C. After 12 hours, the reaction mixture waspoured into 100 mL of ethyl acetate, 100 mL of water, and 25 mL ofsaturated ammonium chloride. The organic layer was separated, dried withmagnesium sulfate, filtered, concentrated, and purified by reverse phaseHPLC (30-100% acetonitrile/water gradient, 0.1% trifluoroacetic acidmodifier) to afford the title compound. ¹H NMR (600 MHz, DMSO-D₆) δ10.40 (s, 1H); 9.34 (d, 1H); 8.70 (d, 1H); 8.28 (s, 1H); 8.00 (d, 1H);7.78 (m, 2H); 7.73 (m, 1H); 7.58 (dd, 1H); 7.38 (d, 1H); 7.26 (d, 1H);3.08 (s, 3H). LRMS (APCI) calculated for C₁₉H₁₅N₂O₃S₂ [M+H]+, 383.0;found 383.1.

Example 16

7-[(2,4-dimethoxybenzyl)amino]-3-(1-methyl-1H-pyrazol-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one

A flask was charged with compound 7 (200.0 mg, 0.492 mmol),1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(205 mg, 0.983 mmol), Pd(dppf)Cl₂ (18. mg, 0.025 mmol) and K₂CO₃ (204mg, 1.48 mmol) then flushed with Ar for 2 min. DMF (4 mL) was added andthe vessel was heated in the Biotage Initiator series microwave for 40min. at 175° C. The mixture was then diluted with EtOAc, washed withwater and brine, then dried over Na₂SO₄. The solution was concentratedin vacuo and purified by reverse phase HPLC (20-100% CH₃CN/water with a0.1% TFA modifier) to afford the title compound 54 ¹H NMR (600 MHz,CD₃OD) δ 8.88 (s, 1H); 8.54 (s, 1H); 8.04 (s, 1H); 7.90 (s, 1H); 7.43(s, 1H); 7.35 (d, 1H); 7.14 (d, 1H); 7.10 (d, 1H); 6.94-6.98 (m, 1H);6.92 (d, 1H); 6.50 (m, 1H); 6.39 (dd, 1H); 5.47 (s, 1H); 4.29 (s, 2H);3.89 (s, 3H); 3.83 (s, 3H); 3.71 (s, 3H). LRMS (APCI) calc'd for(C₂₇H₂₅N₄O₃) [M+H]+, 453.2; found 453.1

Example 18

7-(isopropylamino)-3-(1-methyl-1H-pyrazol-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one

3-chloro-7-(isopropylamino)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one(0.030 g, 0.09 mmol), tris(dibenzylideneacetone)dipalladium (0.004 g,0.004 mmol),1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dixaborolan-2-yl)-1H-pyrazole(0.039 g, 0.19 mmol), potassium fluoride (0.018 g, 0.316 mmol) andtri-t-butylphosphonium tetrafluoroborate (0.003 g, 0.009 mmol) werecombined in a microwave tube. The tube was purged with argon and 2 mL ofdry DMF was added. The solution was stirred and heated to 180° C. in theBiotage Initiator series microwave. After 30 minutes, saturated ammoniumchloride was added and the mixture was extracted with ethyl acetate,washed with brine, dried over magnesium sulfate, filtered, concentratedin vacuo, and purified by reverse phase HPLC (20-70% acetonitrile/watergradient, 0.05% trifluoroacetic acid modifier) to afford the titlecompound. ¹H NMR (600 MHz, CDCl₃) δ 8.93 (d, 1H); 8.64 (bs, 1H); 7.86(s, 1H); 7.75 (s, 1H); 7.45 (d, 1H); 7.39 (d, 1H); 7.14 (m, 2H); 6.85(dd, 1H); 3.93 (s, 3H); 3.76 (septet, 1H); 1.22 (d, 6H). LRMS (APCI)calc'd for (C₂₁H₂₁N₄O) [M+H]+, 345.2; found 345.2.

Example 19

N,N-dimethyl-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]ethanamine

4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.250 g,1,29 mmol), dimethylamino ethyl chloride (0.37 g, 2.58 mmol) andpotassium carbonate (0.534 g, 3.87 mmol) were dissolved in 3 mL of drydimethylformamide. The reaction mixture was heated in a BiotageInitiator series microwave at 190° C. for 1 hour. The reaction mixturewas poured into 300 mL of ethyl acetate and 50 of mL brine. The organiclayer was separated, dried with magnesium sulfate, filtered, andconcentrated to afford the title compound. ¹H NMR (600 MHz, CDCl₃) δ7.76 (s, 1H); 7.72 (s, 1H); 4.22 (t, 2H); 2.94 (s, 3H); 2.86 (s, 3H);2.74 (t, 2H); 1.29 (s, 12H).

Example 20

3-chloro-7-{[(3-methylpyridin-2-yl)methyl]amino}-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one(Compound 56)

7-bromo-3-chloro-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one (0.100 g,0.312 mmol), 2-aminomethyl-3-methylpyridine (0.038 g, 0.312 mmol),copper iodide (0.006 g, 0.031 mmol), potassium carbonate (0.086 g, 0.621mmol), and dl-proline (0.007 g, 0.062 mmol) were combined in a flask.Dimethyl sulfoxide (2.0 mL) was added and argon was bubbled through thesolution for several minutes. The solution was stirred and heated at 70°C. overnight. Once complete the solution was cooled to ambienttemperature, diluted with ethyl acetate and washed with water. Theorganic layer was dried over magnesium sulftate, filtered, concentratedin vacuo and purified by column chromatography (0-40% ethylacetate/hexane gradient) to afford the title compound.

Example 21

3-(1-methyl-1H-pyrazol-4-yl)-7-{[(3-methylpyridin-2-yl)methyl]amino}-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one(Compound 57)

3-chloro-7-{[(3-methylpyridin-2-yl)methyl]amino}-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one(0.170 g, 0.470 mmol), tris(dibenzylideneacetone)dipalladium (0.021 g,0.023 mmol),1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dixaborolan-2-yl)-1H-pyrazole(0.196 g, 0.940 mmol), and tri-t-butylphosphonium tetrafluoroborate(0.013 g, 0.023 mmol) were combined in a flask. The flask was purgedwith argon and 4.0 mL of dry DMF was added. The solution was stirred andheated to 130° C. After 5 hours, the solution was cooled to ambienttemperature. Saturated ammonium chloride was added and the mixture wasextracted with ethyl acetate, washed with brine, dried over magnesiumsulfate, filtered, concentrated in vacuo, and purified by reverse phaseHPLC (20-70% acetonitrile/water gradient, 0.1% trifluoroacetic acidmodifier) to afford the title compound. ¹H NMR (600 MHz, CDCl₃) δ9.13(d, 1H); 8.55 (d, 1H); 8.42 (s, 1H); 8.36 (d, 1H); 8.09 (s, 1H); 7.59(bd, 1H); 7.53 (d, 1H); 7.47 (d, 1H); 7.24-7.21 (m, 3H); 7.05 (t, 1H);7.02 (d, 1H), 4.46 (d, 2H); 3.88 (s, 3H); 2.36 (s, 3H). LRMS (APCI)calc'd for (C₂₅H₂₂N₅O) [M+H]⁺, 408.1; found 408.2.

Example 22

N′-(3-chloro-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)-N-[(2R)-1,4-dioxan-2-ylmethyl]-N-methylsulfamide(Compound 58) Step 1: Benzyl (1,4-dioxan-2-ylmethyl)methylcarbamate

1-(1,4-dioxan-2-yl)-N-methylmethanamine hydrochloride (4.83 g, 29 mmol)was dissolved in 100 mL dichloromethane. Benzyl chloridocarbonate (4.9mL, 35 mmol) and triethylamine (10 mL, 72 mmol) were added. The solutionwas stirred at ambient temperature. After 12 hours, the solution wasconcentrated, then diluted with ethyl acetate, and washed with saturatedsodium bicarbonate and water. The organic layer was separated, driedwith magnesium sulfate, filtered, concentrated in vacuo, and purified bysilica chromatography (0-100% ethyl acetate/hexanes gradient) to affordthe title compound (racemic mixture).

The racemic mixture (6.35 g) was dissolved in 24 mL heptane and 8 mLisopropanol. Material was resolved on chiral AD column (15%isopropanol/heptane) to afford 2.9 g enantiomer A [τ_(R): 9.43 min(analytical chiral HPLC, AD column, 0.46 cm×25 cm cm id, 15%isopropanol/heptane, isocratic, flow rate=0.75 mL/min)] and 2.9 genantiomer B [τ_(R): 10.92 min (analytical chiral HPLC, AD column, 0.46cm×25 cm cm id, 15% isopropanol/heptane, isocratic, flow rate=0.75mL/min)]. LRMS (APCI) calc'd for (C₁₄H₂₀NO₄) [M+H]⁺, 266.1; found,266.2.

Step 2: 1-(1,4-dioxan-2-yl)-N-methylmethanamine hydrochloride

Benzyl (1,4-dioxan-2-ylmethyl)methylcarbamate (Enantiomer A, 2.9 g, 10.9mmol) was dissolved in 50 mL dry ethanol. 10% (w/w) palladium on carbon(0.29 g) and 1.0 mL ION HCl were added. The flask was sealed and flushedwith hydrogen. Stirred solution under a hydrogen balloon. After 12hours, the solution was filtered through celite and concentrated invacuo to afford the title compound. ¹H NMR (600 MHz, D⁶-DMSO) δ 8.64 (s,2H); 3.82-3.75 (m, 2H); 3.69 (d, 1H); 3.64 (d, 1H); 3.59 (m, 1H); 3.44(m, 1H); 3.22 (t, 1H); 2.94-2.84 (m, 2H); 2.51 (s, 3H).

Step 3: tert-butyl{[((2R)-1,4-dioxan-2-ylmethyl)(methyl)amino]sulfonyl}carbamate

1-(1,4-dioxan-2-yl)-N-methylmethanamine hydrochloride (0.760 g, 4,55mmol),N-[1-{[(tert-butoxycarbonyl)amino]sulfonyl}pyridin-4(1H)-ylidene]-N-methylmethanaminium(1.51 g, 5.00 mmol), and triethylamine (1.55 mL, 11.4 mmol) wereslurried in 50 mL dichloromethane and stirred at ambient temperature.After 12 hours, the solution was concentrated in vacuo and purified bysilica chromatography (50-100% ethyl acetate/hexanes gradient) to affordthe title compound. LRMS (APCI) calc'd for (C₁₁H₂₂N₂O₆SNa) [M+Na]+,333.1; found, 333.1.

Step 4: {[((2R)1,4-dioxan-2-ylmethyl)(methyl)amino]sulfonyl}ammoniumtrifluoroacetate

tert-butyl {[(1,4-dioxan-2-ylmethyl)(methyl)amino]sulfonyl}carbamate(1.25 g, 4.03 mmol) was dissolved in 10 mL dichloromethane and 20 mLtrifluoroacetic acid and stirred at ambient temperature. After 2 hours,the solution was concentrated and azeotroped twice with heptane toafford the title compound. LRMS (APCI) calc'd for (C₆H₁₅N₂O₄S) [M+H]+,211.1; found, 211.1.

Step 5:N′-(3-chloro-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)-N-[(2R)-1,4-dioxan-2-ylmethyl]-N-methylsulfamide

7-bromo-3-chloro-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one (1.41 g,4.41 mmol), {[((2R)1,4-dioxan-2-ylmethyl)(methyl)amino]sulfonyl}ammoniumtrifluoroacetate (1.30 g, 4.01 mmol),tris(dibenzylideneacetone)dipalladium (0.183 g, 0.20 mmol),9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (0.347 g, 0.60 mmol),and cesium carbonate (3.91 g, 12.0 mmol) were combined in a dry flask.50 mL dry dioxane was added and argon was bubbled through the solutionfor five minutes. The solution was stirred and heated to 95° C. After 2hours, the solution was concentrated in vacuo, diluted with ethylacetate, and washed with water and brine. The organic layer wasisolated, dried with magnesium sulfate, filtered, concentrated in vacuo,and purified by silica chromatography (0-100% ethyl acetate/hexanesgradient) to afford the title compound. LRMS (APCI) calc'd for(C₂₀H₂₁ClN₃O₅S) [M+H]+, 450.1; found, 450.1.

Example 22A Enantioselective Synthesis of Benzyl[(2S)-1,4-dioxan-2-ylmethyl]methylcarbamate Step 1:(2S)-2-[(benzyloxy)methyl]-1,4-dioxane

(2R)-3-(benzyloxy)propane-1,2-diol (2.00 g, 11.0 mmol) andtetrabutylammonium bromide (708 mg, 2.20 mmol) were dissolved in 50 mLof 1,2-dichloroethane, then 50 mL of a 50% (w/w) aqueous sodiumhydroxide solution was added quickly and the mixture was heated to 50°C. After 18 h, an additional 50 mL of 1,2-dichloroethane and 50 mL of50% (w/w) sodium hydroxide solution was added. After 8 h, additional 50mL of 1,2-dichloroethane was added. After 72 h, the mixture was dilutedin diethyl ether, washed with water and brine, then dried over sodiumsulfate and concentrated. The residue was purified by flash columnchromatography (silica, ethylacetate/hexanes) to afford the titlecompound. ¹H NMR (600 MHz, CDCl₃) δ 7.26-7.35 (m, 5H); 4.51-4.56 (m,2H); 3.72-3.82 (m, 4H); 3.67-3.71 (m, 1H); 3.58-3.64 (m, 1H); 3.38-3.48(m, 3H).

Step 2: benzyl [(2S)-1,4-dioxan-2-ylmethyl]methylcarbamate

A round bottomed flask was charged with(2S)-2-[(benzyloxy)methyl]-1,4-dioxane (1.77 g, 8.48 mmol), 902 mg of10% Pd/C and 50 mL of absolute ethanol. A three-way stopcock fitted witha hydrogen balloon was affixed to the flask, then the flask wasevaporated and back-filled with hydrogen (4×) and stirred under thehydrogen atmosphere overnight. The mixture was filtered through Celiteand concentrated to afford (2S)-1,4-dioxan-2-ylmethanol.

A round bottomed flask was charged with (2S)-1,4-dioxan-2-ylmethanol(115 mg, 0.973 mmol), triethylamine (0.204 mL, 1.46 mmol), and 5 mL ofdichloromethane then cooled to −10° C. Methanesulfonyl chloride (91 mL,1.17 mmol) was added by syringe and the solution was stirred for 30minutes at −10° C. The solution was diluted in dichloromethane, washedwith 1M HCl, and the aqueous layer was extracted with dichloromethane(2×). The combined organic layers were washed with saturated aqueoussodium bicarbonate (2×) and brine, then dried over sodium sulfate andconcentrated to afford (2R)-1,4-dioxan-2-ylmethyl methanesulfonate.

Sodium hydride (29 mg, 0.74 mmol) was suspended in 2 mL ofN,N-dimethylformamide (DMF) and cooled to 0° C. A solution of benzylmethylcarbamate (81 mg, 0.49 mmol) in 2 mL of DMF was added via syringe.After 20 minutes, a solution of (2R)-1,4-dioxan-2-ylmethylmethanesulfonate (191 mg, 0.97 mmol) in 2 mL of DMF was added by syringeand the mixture was heated to 70° C. After 2 h the mixture was cooled toambient temperature, then diluted in diethyl ether, washed with waterand brine, then dried over sodium sulfate and concentrated. The residuewas purified by flash column chromatography (silica,ethylacetate/hexanes) to afford the title compound. LRMS (APCI) calc'dfor (C₁₄H₂₀NO₄) [M+H]+, 266.1; found, 266.2.

Analysis of benzyl [(2S)-1,4-dioxan-2-ylmethyl]methylcarbamate byanalytical HPLC [τ_(R): 10.85 min (analytical chiral HPLC, AD column,0.46 cm×25 cm id, 15% isopropanol/heptane, isocratic, flow rate=0.75mL/min)] and co-injection with Enantiomer A from Example 22 allowed forthe following assignment of stereochemistry for the separatedenantiomers of Example 22, Step 2.

Enantiomer A

benzyl [(2R)-1,4-dioxan-2-ylmethyl]methylcarbamate

Enantiomer B

benzyl [(2S)-1,4-dioxan-2-ylmethyl]methylcarbamate Example 22BEnantioselective Synthesis of{[((2R)1,4-dioxan-2-ylmethyl)(methyl)amino]-sulfonyl}amine Step 1:Epoxide 22B-1

A solution of chloroethanol (13.0 kg, 10.9 L, 162 mole, 3 eq) andBF₃.OEt₂ (342 mL, 2.7 mol, 0.05 eq) in toluene (20 L) was heated to aninternal temp of 36° C. and S-epichlorohydrin added dropwise withcooling at a rate such that the internal temperature remained below 38°C. In 30 min after completion of the addition the reaction wascompleted. The mixture was cooled to 10° C. and sodium hydroxide (12.5L) and water (12.5 L) were added. The bi-phasic mixture was stirred atroom temperature for 2 hours and a further 10 L of water was added todissolve the inorganic solids. The layers were separated and the aqueouslayer was extracted with toluene (20 L). The combined organic layerswere washed with water (15 L) and then concentrated to an approximately50 wt % of product in toluene solution. The resulting viscous solutionwas used directly in the following reaction.

Step 2: Tosylate 22B-2

A solution of conc. aqueous NaOH solution (26.1 L) and water (31.3 L)was heated to 87° C. Crude epoxide 22B-1 (prepared as above; 5.24 kg,38.4 mol) was added and the reaction aged at 90° C. for 30 min. Thereaction was cooled to 22° C. and then diluted with DCM (21 L).p-Toluenesulfonyl chloride (7.46 kg, 38.36 mol) was added and themixture was aged at 22° C. for 16 h. Water (21 L) was added and thephases separated. The aqueous layer was extracted with DCM (2×21 L). Thecombined organic layers were washed with a 5% brine solution (21 L). Theorganic layer was concentrated in vacuo and the residue dissolved intoluene (32 L). Heptane (7 L) was added followed by 22B-2 as seed (100g) and the mixture cooled to 4° C. After ageing for 16 h, the mixturewas filtered and the solids washed with 8:1 heptane/toluene (4 L).Tosylate 22B-2 was isolated as a white solid:

¹H NMR (CDCl₃) δ 2.47 (3H, s), 3.37 (1H, dd, J=9.6, 11.2 Hz), 3.70 (6H,m), 3.97 (1H, dd, J=4.8, 10.4 Hz), 4.03 (1H, dd, J=5.4, 10.6 Hz), 7.37(2H, d, J=8.1 Hz), 7.81 (2H, d, J=8.3 Hz).

Step 3: 1-(1,4-dioxan-2-yl)-N-methylmethanamine hydrochloride

A solution of tosylate 22B-2 (7.76 kg), methylamine in ethanol (62 L ofa 33 wt % solution) and ethanol (62 L) was heated to an internaltemperature of 65° C. for 20 h. The resulting solution was thenconcentrated via atmospheric distillation to a volume of −15 L. Thissolution was held at 50° C. while NaOEt (9.2 L of a 21 wt % solution inethanol; 1.05 equiv) was added, along with MTBE (47 L) each in twoalternating portions. The slurry was then cooled to room temperature andfiltered to remove sodium tosylate. The solids were washed with MTBE(15.5 L). The combined filtrates were solvent switched to isopropanolvia atmospheric distillation. The final volume was ˜30 L. Conc. HCl (2.1L of S.G. 1.18, 1.05 equiv) was added whilst keeping the temperature<60° C. Isopropanol (116 L) was added, and the batch was concentratedvia atmospheric distillation to a total volume of −30 L. This mixturewas held at 50° C. until a slurry formed, then cooled to roomtemperature overnight. The solids were filtered, washed with 1:1heptane:isopropanol (15 L) and dried to give 22B-3 as a white solid.

¹H NMR (400 MHz, MeOD): δ 3.90 (m, 2H), 3.77 (m, 3H), 3.62 (tr d, J=12Hz, J=2.5 Hz, 1H), 3.36 (m, 1H), 3.06 (m, 2H), 2.73 (s, 3H)

Step 4: {[((2R)1,4-dioxan-2-ylmethyl)(methyl)amino]-sulfonyl}amine

To a cold (−20° C.) solution of chlorosulfonylisocyanate (2954 g) indichloromethane (12.6 L) was added benzyl alcohol (2438 g) over 50 min,keeping the temperature below 0° C. A solution of 22B-3 free base wasprepared by stirring 22B-3 (2795 g) with diisopropylethylamine (8.63 kg)in dichloromethane (33.5 L) for 1 h. This was then added to thesulfamoylating reagent over 100 min, keeping the temperature below 0° C.After 45 min, the batch was quenched by the addition of 4M HCl (13 kg)whilst keeping the temperature <5° C. The phases were separated and theDCM layer was washed with water (18.6 kg) and then solvent switched tomethanol and a final volume of 106 L was reached. This solution washydrogenated in the presence of 10% Pd/C (50% wet) (801 g) for 1 h at 1bar of hydrogen. The catalyst was filtered and washed with methanol(2×20 L). The combined filtrates were solvent switched to isopropanol(final volume 32 L). A seed-bed formed. Heptane (72 L) was slowly addedover 1 h. The slurry was aged for 1 h and then filtered, The solids werewashed with 1:2 isopropanol:heptane (10 L) and dried to give 22B-4.

¹H NMR (400 MHz, MeOD): δ 3.79 (m, 3H), 3.71 (m, 2H), 3.59 (tr d, J=2.7Hz, J=12 Hz, 1H), 3.36 (m, 1H), 3.10 (m, 2H), 2.85 (s, 3H).

Example 23

N-[(2R)-1,4-dioxan-2-ylmethyl]-N-methyl-N′-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]sulfamide(Compound 59)

N′-(3-chloro-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)-N-(1,4-dioxan-2-ylmethyl)-N-methylsulfamide(0.500 g, 1.11 mmol),1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(0.692 g, 3.33 mmol), Pd₂(dba)₃ (0.051 g, 0.056 mmol), (tBu₃)PBF₄ (0.032g, 0.11 mmol) and potassium fluoride (0.212 g, 3.66 mmol) were combinedin a dry tube. 5 mL dry DMF was added and argon was bubbled through thesolution for five minutes. The tube was sealed and heated in the BiotageInitiator series microwave to 135° C. for 20 minutes. The solution wasdiluted with ethyl acetate and washed with saturated sodium bicarbonate,water, and brine. The organic layer was dried with magnesium sulfate,filtered, concentrated in vacuo, and purified by silica chromatography(0-100% ethyl acetate/hexanes gradient followed by 0-10%methanol/dichloromethane gradient) to afford the crude compound. Thecrude material was crystallized from a mixture of 10 mL methanol, 40 mLdichloromethane, and 70 mL hexanes to afford the title compound. ¹H NMR(600 MHz, D⁶-DMSO) δ 10.52 (s, 1H); 9.20 (d, 1H); 8.55 (d, 1H); 8.45 (s,1H); 8.13 (s, 1H); 7.95 (d, 1H); 7.75 (d, 1H); 7.55 (d, 1H); 7.32 (d,1H); 7.22 (d, 1H); 3.88 (s, 3H); 3.64-3.60 (m, 2H); 3.58-3.54 (m, 1H);3.54-3.50 (m, 1H); 3.44-3.40 (m, 1H); 3.38-3.34 (m, 1H); 3.14-3.10 (m,3H); 2.77 (s, 3H). LRMS (APCI) calc'd for (C₂₄H₂₆N₅O₅S) [M+H]+, 496.2;found, 496.2.

N-[(2S)-1,4-dioxan-2-ylmethyl]-N-methyl-N′-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]sulfamide(Compound 59S) was prepared using the procedure described in Examples 22and 23, but substituting benzyl[(2S)-1,4-dioxan-2-ylmethyl]methylcarbamate (Enantiomer B from Example22, Step 1) for benzyl [(2R)-1,4-dioxan-2-ylmethyl]methylcarbamate inExample 22, Step 2.

N-[1,4-dioxan-2-ylmethyl]-N-methyl-N′-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]sulfamideracemic mixture (Compound 59RS) was prepared using the proceduredescribed in Examples 22 and 23, but substituting racemic benzyl[1,4-dioxan-2-ylmethyl]methylcarbamate for benzyl[(2R)-1,4-dioxan-2-ylmethyl]methylcarbamate in Example 22, Step 2.

The enantiomeric components of this racemic mixture of the instantcompound were separated by the following procedure: The racemic Compound58RS (0.083 g) was dissolved in a mixture of 2 mL methanol and 18 mLdichloromethane. Material was resolved on chiral OD column (70%isopropanol/heptane) to afford 0.030 g enantiomer A (Compound 59)[τ_(R): 12.8 min (analytical chiral HPLC, OD column, 0.46 cm×25 cm cmid, 60% isopropanol/heptane, isocratic, flow rate=0.75 mL/min)] and0.026 g enantiomer B (Compound 59S) [τ_(R): 15.8 min (analytical chiralHPLC, OD column, 0.46 cm×25 cm cm id, 60% isopropanol/heptane,isocratic, flow rate=0.75 mL/min)].

Example 23A

Pinacolate 23A-1

A solution of 4-bromo-1-methylpyrazole (101 g, 96 wt % pure, 600 mmol)in THF (600 mL) and toluene (600 mL) was degassed three times byvacuum/nitrogen cycles and then left under an atmosphere of nitrogen.Triisopropyl borate (147 g, 181 mL, 1.3 equiv.) was added and themixture was cooled to −74° C. A n-Hexyllithium solution (2.3 M inhexanes, 391 mL) was added slowly via canula over 90 min whilstmaintaining the temperature <−67° C. The resulting viscous pink solutionwas aged for 15 min. Pinacol (106 g, 1.5 equiv.) was added and themixture was warmed to +25° C. over 40 minutes. The mixture is aged for80 min. Water (54 g, 5.0 equiv.) was added dropwise over 10 min to forma white slurry. The slurry was aged for 2.5 h at ambient temperature.The solids were filtered, washed with MTBE (2×250 mL) and dried in vacuoat 35° C. for 16 h. The intermediate 23B-1 was obtained as a dry whitesolid.

Example 23B Alternative synthesis ofN-[(2R)-1,4-dioxan-2-ylmethyl]-N-methyl-N′-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]sulfamide(Compound 59)

A degassed solution ofN′-(3-chloro-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)-N-(1,4-dioxan-2-ylmethyl)-N-methylsulfamide(141.6 g; 34 wt % pure, 48.14 g, 107 mmol), pinacolate 23A-1 (52.50 g)and di(bistriphenylphoshphine)palladium (327 mg, 0.64 mmol, 0.006 eq)was heated to 100° C. for 30 min. The reaction mixture was cooled toambient temperature and 2.0 N NaOH (200 mL) was added followed byEcosorb C941. The mixture was stirred at ambient temperature for onehour and then filtered through 30 g of Solka Floc. The filtrate wasacidified with 70 mL of 5.0 N HCl and then 130 mL of water was added.The resulting slurry was filtered, washed with 2:1H₂O:DMF (500 mL) anddried in vacuo at 60° C. to afford Compound 59.

Example 23C

N-methyl-N′-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-(tetrahydrofuran-3-yl)sulfamideStep 1: N-methyl-N-(tetrahydrofuran-3-yl)sulfamide

A flask was charged withN-tert-butoxycarbonyl-N-[4-(dimethylazaniumylidene)-1,4-dihydropyridin-1-ylsulfonyl]azanide(2.19 g, 7.27 mmol), N-methyltetrahydrofuran-3-aminium chloride (1.00 g,7.27 mmol) and triethyl amine (1.01 mL, 7.27 mmol) in 10 mL of CH₂Cl₂.After 2 h, the solution was concentrated in vacuo and purified by flashcolumn chromatography (10-100% EtOAc/hexanes) to afford tert-butyl{[methyl(tetrahydrofuran-3-yl)amino]sulfonyl}carbamate.

tert-butyl {[methyl(tetrahydrofuran-3-yl)amino]sulfonyl}carbamate (1.47g, 5.23 mmol) was dissolved in 70 mL of CH₂Cl₂ and 45 mL oftrifluoroacetic acid. After 1 h the solution was concentrated in vacuo,diluted in CH₂Cl₂, washed with saturated aqueous NaHCO₃ and brine, thendried over Na₂SO₄. The solution was concentrated in vacuo to afford thetitle compound. ¹H NMR (600 MHz, DMSO-d₆) δ 4.25-4.31 (m, 1H); 3.79-3.84(m, 1H); 3.58-3.66 (m, 2H); 3.47-3.52 (m, 1H); 2.56 (s, 3H), 2.04-2.10(m, 1H); 1.81-1.88 (m, 1H).

Step 2:N′-(3-chloro-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)-N-methyl-N-({3R}-tetrahydrofuran-3-yl)sulfamideandN′-(3-chloro-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)-N-methyl-N-({3R)-tetrahydrofuran-3-yl)sulfamide

7-bromo-3-chloro-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one (665 mg.2.07 mmol), N-methyl-N-(tetrahydrofuran-3-yl)sulfamide (372 mg, 2.06mmol), Pd₂(dba)₃ (95 mg, 0.10 mmol),9,9-dimethyl-4,5-bis(diphenylphosphino) xanthene (XANTPHOS) (179 mg,0.310 mmol) and cesium carbonate (2.02 g, 6.19 mmol) were added to a dryflask through which argon was purged. The flask was charged with 30 mLof dry dioxane and argon was bubbled through the solution for 10minutes. The reaction mixture was heated to 95° C. and stirred underargon. After 2 h, the mixture was cooled to ambient temperature, dilutedin ethyl acetate, washed with saturated aqueous NaHCO₃ and brine, thendried over Na₂SO₄. The solution was concentrated and purified via flashcolumn chromatography (silica, ethylacetate/hexanes) to afford the titlecompound. ¹H NMR (600 MHz, DMSO-d₆) δ 10.59 (s, 1H); 8.97 (d, 1H); 8.50(d, 1H); 7.95 (d, 1H); 7.79 (d, 1H); 7.54 (dd, 1H); 7.40 (d, 1H); 7.22(d, 1H); 4.47-4.53 (m, 1H); 3.75-3.80 (m, 1H); 3.42-3.53 (m, 3H); 2.67(s, 3H); 1.93-2.00 (m, 1H); 1.50-1.72 (m, 1H); LRMS (APCI) calc'd for(C₁₉H₁₉ClN₃O₄S) [M+H]+, 420.1; found, 420.1.

The racemic mixture was dissolved in 5 mg/mL of 5:1methanol/dimethylsulfoxide and resolved on via chiral HPLC (ChiracelOJ-H column, 21 mm×250 mm, 40% methanol/supercritical carbon dioxide,flow rate=50 mL/min, 100 bar outlet pressure) to afford enantiomer A(τ_(R)=6.33 min) and enantiomer B (τ_(R)=7.9 min)

Step 3:N-methyl-N′-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-({3R}-tetrahydrofuran-3-yl)sulfamideandN-methyl-N′-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-({3S}-tetrahydrofuran-3-yl)sulfamide

The separated enantiomers were carried forward in the same manner. Aprocedure is described for Enantiomer B.

N′-(3-chloro-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)-N-methyl-N-(tetrahydrofuran-3-yl)sulfamideEnantiomer B (0.070 g, 0.17 mmol),1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(0.069 g, 0.33 mmol), Pd₂(dba)₃ (0.008 g, 0.0085 mmol), (tBu₃)PBF₄(0.005 g, 0.017 mmol) and potassium fluoride (0.032 g, 0.56 mmol) werecombined in a dry tube. 1.0 mL dry DMF was added and argon was bubbledthrough the solution for five minutes. The tube was sealed and heated ina Biotage Initiator series microwave reactor to 100° C. for 30 minutes.The solution was diluted with ethyl acetate and washed with saturatedsodium bicarbonate. The organic layer was dried with magnesium sulfate,filtered, concentrated in vacuo, and purified by HPLC chromatography(20-100% acetonitrile/water gradient, 0.05% trifluoroacetic acidmodifier) to afford the crude compound. The crude material was purifiedby silica chromatography (0-100% ethyl acetate/hexanes gradient,followed by 0-20% methanol/dichloromethane gradient). The isolatedmaterial was dissolved in minimal 25% methanol/dichloromethane andhexanes were added until precipitation occurred. Precipitate wasfiltered to afford title compound. ¹H NMR (600 MHz, D⁶-DMSO) [10.55 (s,1H); 9.20 (d, 1H); 8.58 (d, 1H); 8.46 (s, 1H); 8.13 (s, 1H); 7.95 (d,1H); 7.75 (d, 1H); 7.52 (dd, 1H); 7.32 (d, 1H); 7.22 (d, 1H); 4.48-4.53(m, 1H); 3.88 (s, 3H); 3.74-3.80 (m, 1H); 3.42-3.54 (m, 3H); 2.68 (s,3H); 1.93-2.00 (m, 1H); 1.65-1.72 (m, 1H). LRMS (APCI) calc'd for(C₂₃H₂₄N₅O₄S) [M+H]+, 466.2; found, 466.2.

The racemic mixture ofN-methyl-N′-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-(tetrahydrofuran-3-yl)sulfamidewas prepared using the above procedure starting with the racemic mixturefrom Step 2.

The following compounds were made according to Scheme 4. Commerciallyunavailable 1-H-pyrazole-4-boronic esters were prepared in a mannersimilar to that described in Example 19. Compounds 136-144 were preparedfrom the respective (2,4-dimethoxybenzyl)amino derivative in a mannersimilar to that described for Example 4B. TABLE 3

Compound R¹ Name MS (M + 1) 60

N-[3-(4-chlorophenyl)-5-oxo-5H- benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide calc'd 411.1 (M + H)+; found 411.0 (M + H)+ 61

N-[3-(2-chlorophenyl)-5-oxo-5H- benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide calc'd 411.1 (M + H)+; found 411.0 (M + H+ 62

N-(5-oxo-3-pyridin-4-yl-5H- benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)methanesulfonamide calc'd 378.1 (M + H)+; found 378.1 (M + H)+ 63

N-(5-oxo-3-pyridin-3-yl-5H- benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)methanesulfonamide calc'd 378.1 (M + H)+; found 378.1 (M + H)+ 64

N-[5-oxo-3-(1H-pyrazol-3-yl)-5H- benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide calc'd 367.1 (M + H)+; found 367.1 (M + H)+ 65

N-[3-(3-chlorophenyl)-5-oxo-5H- benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide calc'd 411.1 (M + H)+; found 411.0 (M + H)+ 66

N-(5-oxo-3-pyrimidin-5-yl-5H- benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)methanesulfonamide calc'd 379.1 (M + H)+; found 379.1 (M + H)+ 67

N-(5-oxo-3-quinolin-6-yl-5H- benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)methanesulfonamide calc'd 428.1 (M + H)+; found 428.1 (M + H)+ 68

N-[3-(3-furyl)-5-oxo-5H- benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide calc'd 367.1 (M + H)+; found 367.1 (M + H)+ 69

N-[3-(2-furyl)-5-oxo-5H- benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide calc'd 367.1 (M + H)+; found 367.1 (M + H)+ 70

N-[3-(4-fluorophenyl)-5-oxo-5H- benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide calc'd 395.1 (M + H)+; found 395.1 (M + H)+ 71

N-[3-(3-fluorophenyl)-5-oxo-5H- benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide calc'd 395.1 (M + H)+; found 395.1 (M + H)+ 72

N-[3-(2-fluorophenyl)-5-oxo-5H- benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide calc'd 395.1 (M + H)+; found 395.1 (M + H)+ 73

N-(5-oxo-3-quinolin-8-yl-5H- benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)methanesulfonamide calc'd 428.1 (M + H)+; found 428.2 (M + H)+ 74

N-(5-oxo-3-quinolin-3-yl-5H- benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)methanesulfonamide calcd 428.1 (M + H)+; found 428.1 (M + H)+ 75

N-(5-oxo-3-quinolin-5-yl-5H- benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)methanesulfonamide calc'd 428.1 (M + H)+; found 428.1 (M + H)+ 76

N-[3-(2,4-dichlorophenyl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7- yl]methanesulfonamide calc'd 445.0(M + H)+; found 445.0 (M + H)+ 77

N-(3-imidazo[1,2-a]pyrazin-3-yl-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin- 7-yl)methanesulfonamide calc'd418.1 (M + H)+; found 418.1 (M + H)+ 78

N-[5-oxo-3-(1,3-thiazol-4-yl)-5H- benzol[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide calc'd 384.0 (M + H)+; found 384.0 (M + H)+ 79

N-(3-isothiazol-4-yl-5-oxo-5H- benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)methanesulfonamide calc'd 384.0 (M + H)+; found 384.0 (M + H)+ 80

N-[3-(1-methyl-1H-pyrazol-4-yl)-5- oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide calc'd 381.1 (M + H)+; found 380.7(M + H)+ 81

N-(3-isothiazol-5-yl-5-oxo-5H- benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)methanesulfonamide calc'd 384.0 (M + H)+; found 384.0 (M + H)+ 82

N-[3-(3,5-dimethylisoxazol-4-yl)-5- oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide calc'd 396.1 (M + H)+; found 396.1(M + H)+ 83

N-[5-oxo-3-(1H-pyrazol-4-yl)-5H- benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide calc'd 367.1 (M + H)+; found 366.7 (M + H)+ 84

methyl (4-{7-[(methylsulfonyl)amino]- 5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-3-yl}-1H-pyrazol-1-yl)acetate calc'd 439.1 (M + H)+; found438.7 (M + H)+ 85

ethyl 3-(4-{7-[(methylsulfonyl)amino]-5-oxo-5H-benzo[4,5]cyclohepta[1,2- b]pyridin-3-yl}-1H-pyrazol-1-yl)propanoate calc'd 467.1 (M + H)+; found 466.6 (M + H)+ 86

N-(3-{1-[2-(dimethylamino)ethyl]-1H- pyrazol-4-yl}-5-oxo-5H-benzol[4,5]cyclohepta[1,2-b]pyridin-7- yl)methanesulfonamide, 3TFA or3HCl calc'd 438.2 (M + H)+; found 437.7 (M + H)+ 87

N-[3-(1-isobutyl-1H-pyrazol-4-yl)-5- oxo-5H-benzol[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide calc'd 423.1 (M + H)+; found 422.7(M + H)+ 88

N-[5-oxo-3-(1-propyl-1H-pyrazol-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin- 7-yl]methanesulfonamide calc'd409.1 (M + H)+; found 408.7 (M + H)+ 89

N-(3-{1-[3-(dimethylamino)propyl]-1H- pyrazol-4-yl}-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7- yl)methanesulfonamide calc'd 452.2(M + 1-1)+; found 451.7 (M + H)+ 90

N-{3-[1-(2-morpholin-4-yl-2-oxoethyl)- 1H-pyrazol-4-yl]-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7- yl}methanesulfonamide calc'd 494.1(M + H)+; found 493.6 (M + H)+ 91

N-{5-oxo-3-[1-(2-pyrrolidin-1-ylethyl)-benzo[4,5]cyclohepta[1,2-b]pyridin-7- yl}methanesulfonamide calc'd 464.2(M + H)+; found 463.7 (M + H)+ 92

N-[3-(1-benzyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin- 7-yl]methanesulfonamide calc'd457.1 (M + H)+; found 456.7 (M + H)+ 93

(4-{7-[(methylsulfonyl)amino]-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin- 3-yl}-1H-pyrazol-1-yl)acetic acidcalc'd 425.1 (M + H)+; found 424.7 (M + H)+ 94

3-(4-{7-[(methylsulfonyl)amino]-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin- 3-yl}-1H-pyrazol-1-yl)propanoicacid calc'd 439.1 (M + H)+; found 439.1 (M + H)+ 95

N-(3-{7-[(methylsulfonyl)amino]-5- oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-3-yl}phenyl)-3-piperidin- 1-ylpropanamide calc'd 531.2 (M +H)+; found 531.2 (M + H)+ 96

N-(4-{7-[(methylsulfonyl)amino]-5- oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-3- yl}phenyl)methanesulfonamide calc'd 470.1 (M + H)+; found470.1 (M + H)+ 97

N-(3-{1-[3-(benzyloxy)propyl]-1H- pyrazol-4-yl}-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin- 7-yl)methanesulfonamide calc'd 515.2(M + H)+; found 515.2 (M + H)+ 98

N-[3-(1-isopropyl-1H-pyrazol-4-yl)- 5-oxo-5H-benzol[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide calc'd 409.1 (M + H)+; found 409.1(M + H)+ 99

N-{3-[1-(3-methylbutyl)-1H- pyrazol-4-yl]-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin- 7-yl}methanesulfonamide calc'd 437.2(M + H)+; found 437.2 (M + H)+ 100

N-[3-(1-cyclopentyl-1H-pyrazol-4- yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin- 7-yl]methanesulfonamide cal'd 435.1(M + H)+; found 435.1 (M + H)+ 101

N-{3-[1-(3-hydroxypropyl)-1H- pyrazol-4-yl]-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin- 7-yl}methanesulfonamide calc'd 425.1(M + H)+; found 425.1 (M + H)+ 102

3-{7-[(methylsulfonyl)amino]-5- oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-3-yl}benzoic acid calc'd 421.2 (M + H)+; found 420.9 (M + H)+103

3-(2,3-dihydro-1H-pyrazolo[1,2- a]pyrazol-4-ium-6-yl)-7-[(methylsulfonyl)amino]-5-oxo-5H- benzo[4,5]cyclohepta[1,2- b]pyridiniumbis(trifluoroacetate) calc'd 408.1 (M + H)+; found 407.1 (M + H)+ 104

methyl 2-(4-{7- [(methylsulfonyl)amino]-5-oxo-5H-benzol[4,5]cyclohepta[1,2-b]pyridin- 3-yl}-1H-pyrazol-1-yl)propanoatecalc'd 453.1 (M + H)+; found 453.1 (M + H)+ 105

N-{3-[1-(3,3-dimethyl-2-oxobutyl)- 1H-pyrazol-4-yl]-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin- 7-yl}methanesulfonamide calc'd 465.2(M + H)+; found 465.2 (M + H)+ 106

4-{7-[(methylsulfonyl)amino]-5- oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-3-yl}benzoic acid calc'd 421.1 (M + H)+; found 421.2 (M + H)+107

N-[3-(3-nitrophenyl)-5-oxo-5H- benzol[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide calc'd 422.1 (M + H)+; found 422.1 (M + H)+ 108

N-[3-(4-nitrophenyl)-5-oxo-5H- benzol[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide calc'd 422.1 (M + H)+; found 422.1 (M + H)+ 109

N-isobutyl-3-{7- [(methylsulfonyl)amino]-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin- 3-yl}benzamide calc'd 476.2 (M +H)+; found 476.1 (M + H)+ 110

3-{7-[(methylsulfonyl)amino]-5- oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-3-yl}-N-(2-morpholin-4- ylethyl)benzamide calc'd 533.2 (M +H)+; found 533.1 (M + H)+ 111

N-[2-(1-methylpyrrolidin-2- yl)ethyl]-3-{7-[(methylsulfonyl)amino]-5-oxo-5H- benzo[4,5]cyclohepta[1,2-b]pyridin-3-yl}benzamide calc'd 531.2 (M + H)+; found 531.0 (M + H)+ 112

N-[(1-methyl-LH-pyrazol-4- yl)methyl]-3-{7-[(methylsulfonyl)amino]-5-oxo-5H- benzo[4,5]cyclohepta[1,2-b]pyridin-3-yl}benzamide calc'd 514.1 (M + H)+; found 513.9 (M + H)+ 113

N-{3-[1-(3-hydroxypropyl)-1H- pyrazol-4-yl]-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin- 7-yl}methanesulfonamide calc'd 425.1(M + H)+; found 425.1 (M + H)+ 114

N-[(5-methylpyrazin-2-yl)methyl]-3- {7-[(methylsulfonyl)amino]-5-oxo-5H-benzo[4,5]cyclohepta[1,2- b]pyridin-3-yl}benzamide calc'd 526.1 (M +H)+; found 526.1 (M + H)+ 115

N-isobutyl-4-{7- [(methylsulfonyl)amino]-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin- 3-yl}benzamide calc'd 476.2 (M +H)+; found 476.1 116

N-[(1-methyl-1H-pyrazol-4- yl)methyl]-4-{7-[(methylsulfonyl)amino]-5-oxo-5H- benzo[4,5]cyclohepta[1,2-b]pyridin-3-yl}benzamide calc'd 514.1 (M + H)+; found 514.2 (M + H)+

TABLE 3A MS Compound Structure Name (M+1) 117

2-methyl-N-[3-(1- methyl-1H-pyrazol-4- yl)-5-oxo-5H-benzo[4,5]cyclohepta[1, 2-b]pyridin-7- yl]propane-2-sulfonamide (M+1)calc'd 423.1 (M+H)+; found 422.7 (M+H)+ 118

N,N-dimeethyl-N′-[3-(1- methyl-1H-pyrazol-4- yl)-5-oxo-5H-benzo[4,5]cyclohepta[1, 2-b]pyridin-7- yl]sulfamide calc'd 410.1 (M+H)+;found 409.7 (M+H)+ 119

N-benzyl-N-methyl-N′- [3-(1-methyl-1H- pyrazol-4-yl)-5-oxo- 5H-benzo[4,5]cyclohepta[1, 2-b]pyridin-7- yl[sulfamide calc'd 486.2 (M+H)+;found 485.7 (M+H)+ 120

N,N-diethyl-N′-[3-(1- methyl-1H-pyrazol-4- yl)-5-oxo-5H-benzo[4,5]cyclohepta[1, 2-b]pyridin-7- yl]sulfamide calc'd 438.2 (M+H)+;found 438.1 (M+H)+ 121

N-[3-(1-methyl-1H- pyrazol-4-yl)-5-oxo- 5H- benzo[4,5]cyclohepta[1,2-b]pyridin-7- yl]pyrrolidine-1- sulfonamide calc'd 436.1 (M+H)+; found436.1 (M+H)+ 122

N-ethyl-N-methyl-N′- [3-(1-methyl-1H- pyrazol-4-yl)-5-oxo- 5H-beenzo[4,5]cyclohepta[1, 2-b]pyridin-7- yl]sulfamide calc'd 424.1(M+H)+; found 424.1 (M+H)+ 123

N,N-dimethyl-N′-[5- oxo-3-(1-propyl-1H- pyrazol-4-yl)-5H-benzo[4,5]cyclohepta[1, 2-b]pyridin-7- yl]sulfamide calc'd 438.2 (M+H)+;found 438.2 (M+H)+ 124

N,N-dimeethyl-N′-{3-[1- (2-morpholin-4-yl-2- oxoethyl)-1H-pyrazol-4-yl]-5-oxo-5H- benzo[4,5]cyclohepta[1, 2-b]pyridin-7- yl}sulfamidecalc'd 523.2 (M+H)+; found 523.2 (M+H)+ 125

N′-(3-{1-[3- (dimethylamino)propyl]- 1H-pyrazol-4-yl}-5- oxo-5H-benzo[4,5]cyclohepta[1, 2-b]pyridin-7-yl)-N,N- dimethylsulfamide calc'd481.2 (M+H)+; found 481.2 (M+H)+ 126

N-isopropyl-N-methyl- N′-[3-(1-methyl-1H- pyrazol-4-yl)-5-oxo- 5H-benzo[4,5]cyclohepta[1, 2-b]pyridin-7- yl]sulfamide calc'd 438.2 (M+H)+;found 438.2 (M+H)+ 127

7-(5-methyl-1,1- dioxido-1,2,5- thiadiazolin-2-yl)-3-(1-methyl-1H-pyrazol- 4-yl)-5H- benzo[4,5]cyclohepta]1,2-b]pyridin-5-one calc'd 422.1 (M+H)+; found 422.1 (M+H)+ 128

N-methyl-N′-[3-(1- methyl-1H-pyrazol-4- yl)-5-oxo-5H-benzo[4,5]cyclohepta[1, 2-b]pyridin-7- yl]sulfamide calc'd 382.1 (M+H)+;found 382.1 (M+H)+ 129

1,1,1-trifluoro-N-[3-(1- methyl-1H-pyrazol-4- yl)-5-oxo-5H-benzo[4,5]cyclohepta[1, 2-b]pyridin-7- yl]methanesulfonamide calc'd435.1 (M+H)+; found 434.6 (M+H)+ 130

7-[(2,4- dimethoxybenzyl)amino]- 3-(3-thienyl)-5H-benzo[4,5]cyclohepta[1, 2-b]pyridin-5-one calc'd 455.1 (M+H)+; found455.2 (M+H)+ 131

7-[(2,4- dimethoxybenzyl)amino]- 3-(1H-pyrazol-3-yl)- 5H-benzo[4,5]cyclohepta[1, 2-b]pyridin-5-one calc'd 439.2 (M+H)+; found439.2 (M+H)+ 132

7-[(2,4- dimethoxybenzyl)amino]- 3-(5-methyl-2- thienyl)-5H-benzo[4,5]cyclohepta[1, 2-b]pyridin-5-one calc'd 469.2 (M+H)+; found469.1 (M+H)+ 133

3-(1-benzothien-3-yl)- 7-[(2,4- dimethoxybenzyl)amino]- 5H-benzo[4,5]cyclohepta[1, 2-b]pyridin-5-one calc'd 505.2 (M+H)+; found505.1 (M+H)+ 134

N-(4-{7-[(2,4- dimthoxybenzyl)amino]- 5-oxo-5H- benzo[4,5]cyclohepta[1,2-b]pyridin-3- yl}phenyl)acetamide calc'd 506.2 (M+H)+; found 506.2(M+H)+ 135

4-{7-[(2,4- dimethoxybenzyl)amino]- 5-oxo-5H- benzo[4,5]cyclohepta[1,2-b]pyridin-3- yl}benzoic acid calc'd 493.2 (M+H)+; found 493.1 (M+H)+136

7-ammino-3-(3-thienyl)- 5H- benzo[4,5]cyclohepta[1, 2-b]pyridin-5-onecalc'd 305.1 (M+H)+; found 305.1 (M+H)+ 137

7-amino-3-(2-thienyl)- 5H- benzo[4,5]cyclohepta[1, 2-b]pyridin-5-onecalc'd 305.1 (M+H)+; found 305.1 (M+H)+ 138

7-amino-3-(1-H- pyrazol-4-yl)-5H- benzo[4,5]cyclohepta[1,2-b]pyridin-5-one; isolated as 3HCl salt calc'd 289.1 (M+H)+; found289.1 (M+H)+ 139

7-amino-3-(1-methyl- 1H-pyrazol-4-yl)-5H- benzo[4,5]cyclohepta[1,2-b]pyridin-5-one; isolated as 3HCl salt calc'd 303.1 (M+H)+; found303.1 (M+H)+ 140

7-amino-3-(1H- pyrazol-3-yl)-5H- benzo[4,5]cyclohepta[1,2-b]pyridin-5-one; isolated as 3HCl salt calc'd 289.1 (M+H)+; found289.1 (M+H)+ 141

7-amino-3-(5-methyl-2- thienyl)-5H- benzo[4,5]cyclohepta]1,2-b]pyridin-5-one calc'd 319.1 (M+H)+; found 319.1 (M+H)+ 142

7-amino-3-(1- benzothien-3-yl)-5H- benzo[4,5]cyclohepta[1,2-b]pyridin-5-one calc'd 355.1 (M+H)+; found 355.1 (M+H)+ 143

N-[4-(7-amino-5-oxo- 5H- benzo[4,5]cyclohepta[1, 2-b]pyridin-3-yl)phenyl]acetamide calc'd 356.1 (M+H)+; found 356.1 (M+H)+ 144

4-(7-amino-5-oxo-5H- benzo[4,5]cyclohepta[1, 2-b]pyridin-3- yl)benzoicacid calc'd 343.1 (M+H)+; found 343.1 (M+H)+ 145

7-hydroxy-3-(3- thienyl)-5H- benzo[4,5]cyclohepta[1, 2-b]pyridin-5-onecalc'd 306.1 (M+H)+; found 306.1 (M+H)+ 146

7- [(cyclohexylmethyl) amino]-3-(1-methyl- 1H-pyrazol-4-yl)-5H-benzo[4,5]cyclohepta [1,2-b]pyridin-5-one calc'd 399.2 (M+H)+; found399.2 (M+H)+ 147

7-[(4- fluorobenzyl)amino]- 3-(1-methyl-1H- pyrazol-4-yl)-5H-benzo[4,5]cyclohepta 1,2-b]pyridin-5-one calc'd 411.2 (M+H)+; found411.1 (M+H)+ 148

3-(1-methyl-1H- pyrazol-4-yl)-7-vinyl- 5H- benzo[4,5]cyclohepta[1,2-b]pyridin-5-one calc'd 314.1 (M+H)+; found 314.1 (M+H)+ 149

7-[(2,4- difluorobenzyl)amino]- 3-(1-methyl-1H- pyrazol-4-yl)-5H-benzo[4,5]cyclohepta [1,2-b]pyridin-5-one calc'd 429.1 (M+H)+; found429.1 (M+H)+ 150

3-(1-methyl-1H- pyrazol-4-yl)-7-[(2- phenylethyl)amino]- 5H-benzo[4,5]cyclohepta [1,2-b]pyridin-5-one calc'd 407.2 (M+H)+; found407.2 (M+H)+ 151

7-[(3,4- difluorobenzyl)amino]- 3-(1-methyl-1H- pyrazol-4-yl)-5H-benzo[4,5]cyclohepta [1,2-b]pyridin-5-one calc'd 429.1 (M+H)+; found429.2 (M+H)+ 152

7-[(4- methylbenzyl)amino]- 3-(1-methyl-1H- pyrazol-4-yl)-5H-benzo[4,5]cyclohepta [1,2-b]pyridin-5-one calc'd 407.2 (M+H)+; found407.2 (M+H)+ 153

7-[(2,4- dimethylbenzyl)amino]- 3-(1-methyl-1H- pyrazol-4-yl)-5H-benzo[4,5]cyclohepta [1,2-b]pyridin-5-one calc'd 421.2 (M+H)+; found421.2 (M+H)+ 154

7-{[2-(4- fluorophenyl)ethyl]amino}-3-(1-methyl- 1H-pyrazol-4-yl)-5H-benzo[4,5]cyclohepta 1,2-b]pyridin-5-one calc'd 425.2 (M+H)+; found425.2 (M+H)+ 155

7-(butylammino)-3-(1- methyl-1H-pyrazol-4- yl)-5H- benzo[4,5]cyclohepta[1,2-b]pyridin-5-one calc'd 359.2 (M+H)+; found 359.2 (M+H)+ 156

3-(1-methyl-1H- pyrazol-4-yl)-7- (propylamino)-5H- benzo[4,5]cyclohepta[1,2-b]pyridin-5-one calc'd 345.2 (M+H)+; found 345.2 (M+H)+ 157

7-[(3- methylbutyl)amino]- 3-(1-methyl-1H- pyrazol-4-yl)-5H-benzo[4,5]cyclohepta [1,2-b]pyridin-5-one calc'd 373.2 (M+H)+; found373.2 (M+H)+ 158

7-(isopropylamino)- 3-(1-methyl-1H- pyrazol-4-yl)-5H-benzo[4,5]cyclohepta [1,2-b]pyridin-5-one calc'd 345.2 (M+H)+; found345.2 (M+H)+ 159

7-[(1,3-benzodioxol- 5-ylmethyl)amino]-3- (1-methyl-1H-pyrazol-4-yl)-5H- benzo[4,5]cyclohepta [1,2-b]pyridin-5-one Calc'd 437.2(M+H)+; found 437.2 (M+H)+ 160

7-(isobutylamino)-3- (1-methyl-1H- pyrazol-4-yl)-5H-benzo[4,5]cyclohepta [1,2-b]pyridin-5-one Calc'd 359.2 (M+H)+; found359.2 (M+H)+ 161

7-[(2- methylbenyl)amino]- 3-(1-methyl-1H- pyrazol-4-yl)-5H-benzo[4,5]cyclohepta [1,2-b]pyridin-5-one calc'd 407.2 (M+H)+; found407.2 (M+H)+ 162

3-(1-methyl-1H- pyrazol-4-yl)-7-{[2- (trifluoromethyl) benzyl]amino}-5H-benzo[4,5]cyclohepta [1,2-b]pyridin-5-one calc'd 461.2 (M+H)+; found461.1 (M+H)+ 163

7-[(biphenyl-2- ylmethyl)amino]-3- (1-methyl-1H- pyrazol-4-yl)-5H-benzo[4,5]cyclohepta [1,2-b]pyridin-5-one Calc'd 469.2 (M+H)+; found469.1 (M+H)+ 164

7-[(2- chclorobenzyl)amino]-3- (1-methyl-1H-pyrazol- 4-yl)-5H-benzo[4,5]cyclohepta[1, 2-b]pyridin-5-one Calc'd 427.1 (M+H)+; found427.1 (M+H)+ 165

7-[(2,3- dimethylbenzyl)amino]- 3-(1-methyl-1H- pyrazol-4-yl)-5H-benzo[4,5]cyclohepta[1, 2-b]pyridin-5-one calc'd 421.2 (M+H)+; found421.2 (M+H)+ 166

N-methyl-N′-[3-(1- methyl-1H-pyrazol-4- yl)-5-oxo-5H-benzo[4,5]cyclohepta[1, 2-b]pyridin-7-yl]-N- (tetrahydrofuran-3-yl)sulfamide calc'd 466.1 (M+H)+; found 466.1 (M+H)+ 167

N′-(3-{1-[3- (benzyloxy)propyl]- 1H-pyrazol-4-yl}-5- oxo-5H-benzo[4,5]-cyclohepta[1,2- b]pyridin-7-yl)-N,N- dimethylsulfamide calc'd 544.2(M+H)+; found 544.2 (M+H)+ 168

N′-{3-[1-(3- hydroxypropyl)-1H- pyrazol-4-yl]-5-oxo- 5H-benzo[4,5]cyclohepta[1, 2-b]pyridin-7-yl]-N,N- dimethylsulfamide calc'd454.2 (M+H)+; found 454.1 (M+H)+ 169

7-[(imidazo[1,2- a]pyridin-3- ylmethyl)amino]-3-(1-meethyl-1H-pyrazol-4- yl)-5H- benzo[4,5]cyclohepta]1, 2-b]pyridin-5-onecalc'd 433.2 (M+H)+; found 433.2 (M+H)+ 170

N,N-dimeethyl-N′-(3-{1- [(3-meethyloxetan-3- yl)methyl]-1H-pyrazol-4-yl}-5-oxo-5H- benzo[4,5]cyclohepta[1, 2-b]pyridin-7- yl)sulfamidecalc'd 480.2 (M+H)+; found 480.2 (M+H)+ 171

7-{[(1-methyl-5- oxopyrrolidin-2- yl)methyl]amino}-3- (1-methyl-1H-pyrazol-4-yl)-5H- benzo[4,5]cyclohepta [1,2-b]pyridin-5-one calc'd 414.2(M+H)+; found 414.1 (M+H)+ 172

3,7-bis(1-methyl-1H- pyrazol-4-yl)-5H- benzo[4,5]cyclohepta[1,2-a]pyridin-5-one Calc'd 368.1 (M+H)+; found 368.2 (M+H)+ 173

3-(1-methyl-1H- pyrazol-4-yl)-7-(1H- pyrrol-2-yl)-5H-benzo[4,5]cyclohepta [1,2-b]pyridin-5-one Calc'd 353.1 (M+H)+; found353.1 (M+H)+ 174

3-(1-methyl-1H- pyrazol-4-yl)-7-{[(3- methylpyridin-4- yl)methyl]amino}-5H- benzo[4,5]cyclohepta [1,2-b]pyridin-5-one Calc'd 408.2 (M+H)+; found408.2 (M+H)+ 175

3-(1-methyl-1H- pyrazol-4-yl)-7-(1H- pyrazol-3-yl)-5H-benzo[4,5]cyclohepta [1,2-b]pyridin-5-one calc'd 354.1 (M+H)+; found354.2 (M+H)+ 176

N-[3-(1-methyl-1H- pyrazol-4-yl)-5-oxo- 5H- benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]- 2- (trifluoromethyl) benzamide calc'd 475.1(M+H)+; found 475.1 (M+H)+ 177

7-{[(1- ethylpyrrolidin-2- yl)methyl]amino}-3- (1-methyl-1H-pyrazol-4-yl)-5H- benzo[4,5]cyclohepta [1,2-b]pyridin-5-one Calc'd 414.2(M+H)+; found 414.2 (M+H)+ 178

7-[(2,6- dimethylbenzyl)amino]- 3-(1-methyl-1H- pyrazol-4-yl)-5H-benzo[4,5]cyclohepta [1,2-b]pyridin-5-one Calc'd 421.2 (M+H)+; found421.2 (M+H)+ 179

N-methyl-N-[(1- methyl-5- oxopyrrolidin-2- yl)methyl]-N′-[3-(1-methyl-1H-pyrazol-4- yl)-5-oxo-5H- benzo[4,5]- cyclohepta[1,2-b]pyridin-7- yl]sulfamide calc'd 507.2 (M+H)+; found 507.2 (M+H)+ 180

N-methyl-N-[(1- methyl-1H-imidazol- 2-yl)methyl]-N′-[3- (1-methyl-1H-pyrazol-4-yl)-5-oxo- 5H- benzo[4,5]cyclohepta [1,2-b]pyridin-7-yl]sulfamide calc'd 490.2 (M+H)+; found 490.2 (M+H)+ 181

N-methyl-N′-[3-(1- methyl-1H-pyrazol-4- yl)-5-oxo-5H-benzo[4,5]cyclohepta [1,2-b]pyridin-7-yl]- N-(tetrahydro-2H- pyran-2-ylmethyl)sulfamide calc'd 494.2 (M+H)+; found 494.2 (M+H)+ 182

N-[3-(1-methyl-1H- pyrazol-4-yl)-5-oxo- 5H- benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]- 2- (trifluoromethyl) benzene-sulfonamide calc'd511.1 (M+H)+; found 511.1 (M+H)+ 183

N-[3-(1-methyl-1H- pyrazol-4-yl)-5-oxo- 5H- benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]- N′-[2- (trimethyl) benzyl]sulfamide calc'd 540.1(M+H)+; found 540.2 (M+H)+ 184

methyl 4-(7-{[(3- methylpyridin-2- yl)methyl]amino}-5- oxo-5H-benzo[4,5]cyclohepta [1,2-b]pyridin-3- yl)benzoate calc'd 462.2 (M+H)+;found 462.2 (M+H)+ 185

N-[3-(1-meethyl-1H- pyrazol-4-yl)-5-oxo- 5H- benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]- N′-(tetrahydrofuran- 3-yl)sulfamide calc'd 452.1(M+H)+; found 452.2 (M+H)+ 186

tert-butyl 4-[4-(7- {[(3-methylpyridin-2- yl)methyl]amino}-5- oxo-5H-benzo[4,5]cycloheepta [1,2-b]pyridin-3- yl)phenyl]piperazine-1-carboxylate calc'd 588.3 (M+H)+; found 588.3 (M+H)+ 187

7-{[(3-methylpyridin- 2-yl)meethyl]amino}- 3-(4-piperazin-1-ylphenyl)-5H- benzo[4,5]cyclohepta [1,2-b]pyridin-5-one calc'd 488.2(M+H)+; found 488.3 (M+H)+ 188

3-[3- (dimethylamino) phenyl]-7-{[(3- methylpyridin-2- yl)methyl]amino}-5H- benzo[4,5]cyclohepta [1,2-b]pyridin-5-one Calc'd 447.2 (M+H)+; found447.2 (M+H)+ 189

7-{[(3-methylpyridin- 2-yl)methyl]amino}- 3-pyridin-4-yl-5H-benzo[4,5]cyclohepta [1,2-b]pyridin-5-one Calc'd 405.2 (M+H)+; found405.2 (M+H)+ 190

N-[3-(1-methyl-1H- pyrazol-4-yl)-5-oxo- 5H- benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]- N′-(tetrahydrofuran- 3-ylmethyl)sulfamide calc'd466.1 (M+H)+; found 466.2 (M+H)+ 191

N-[(1-methyl-1H- pyrazol-4-yl)methyl]- N′-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo- 5H- benzo[4,5]cyclohepta [1,2-b]pyridin-7-yl]sulfamide calc'd 476.1 (M+H)+; found 476.2 (M+H)+ 192

N-[3-(1-methyl-1H- pyrazol-4-yl)-5-oxo- 5H- benzo[4,5]cyclohepta[1,2-b]pyridin-7- yl]morpholine-4- sulfonamide calc'd 452.1 (M+H)+;found 452.2 (M+H)+ 193

N-[3-(1-methyl-1H- pyrazol-4-yl)-5-oxo- pyrazol-4-yl)-5-oxo- 5H-benzo[4,5]cyclohepta [1,2-b]pyridin-7-yl]- 2-(trifluoromethyl)- 5,6-dihydroimidazo[1,2- a]pyrazine-7(8H)- sulfonamide calc'd 556.1 (M+H)+;found 556.1 (M+H)+ 194

N-isobutyl-4-(7-{[(3- methylpyridin-2- yl)methyl]amino}-5- oxo-5H-benzo[4,5]cyclohepta [1,2-b]pyridin-3- yl)benzamide calc'd 503.2 (M+H)+;found 503.2 (M+H)+ 195

7-{[(3-methylpyridin- 2-yl)methyl]amino}- 3-pyrimidin-5-yl-5H-benzo[4,5]cyclohepta [1,2-b]pyridin-5-one Calc'd 406.2 (M+H)+; found406.1 (M+H)+ 196

4-(7-{[(3- methylpyridin-2- yl)methyl]amino}-5- oxo-5H-benzo[4,5]cyclohepta [1,2-b]pyridin-3-yl)- N-phenylbenzamide Calc'd523.2 (M+H)+; found 523.2 (M+H)+ 197

3-(6-fluoropyridin-3- yl)-7-{[(3- methylpyridin-2- yl)methyl]amino}- 5H-benzo[4,5]cyclohepta [1,2-b]pyridin-5-one Calc'd 423.2 (M+H)+; found423.2 (M+H)+ 198

N-[3- (dimethylamino) propyl]-4-(7-{[(3- methylpyridin-2-yl)methyl]amino}-5- oxo-5H- benzo[4,5]cyclohepta [1,2-b]pyridin-3-yl)benzamide calc'd 532.3 (M+H)+; found 532.3 (M+H)+ 199

3-(1-methyl-1H- pyrazol-4-yl)-7- [(tetrahydro-2H- pyran-4-ylmethyl)amino]-5H- benzo[4,5]cyclohepta [1,2-b]pyridin-5-one calc'd401.2 (M+H)+; found 401.2 (M+H)+ 200

3-pyridin-4-yl-7- [(tetrahydro-2H- pyran-4- ylmethyl)amino]-5H-benzo[4,5]cyclohepta [1,2-b]pyridin-5-one calc'd 398.2 (M+H)+; foundd398.2 (M+H)+ 201

7-[(1,4-dioxan-2- ylmethyl)amino]-3- (1-methyl-1H- pyrazol-4-yl)-5H-benzo[4,5]cyclohepta [1,2-b]pyridin-5-one calc'd 403.2 (M+H)+; found403.2 (M+H)+ 201A

7-[(2-morpholin-4-yl- 2-oxoethyl)amino]-3- [1-(2,2,2-trifluoroethyl)-1H- pyrazol-4-yl]-5H- benzo[4,5]cyclohepta[1,2-b]pyridin-5-one calc'd [M+H]⁺, 498.2; found 498.1. 201B

3-(1-methyl-1H- pyrazol-4-yl)-7-{[2-(3- oxomorpholin-4-yl)ethyl]amino}-5H- benzo[4,5]cyclohepta[1, 2-b]pyridin-5-one calc'd[M+H]⁺, 430.2; found 430.1. 201C

3-fluoro-N-[3-(1- methyl-1H-pyrazol-4- yl)-5-oxo-5H-benzo[4,5]cyclohepta [1,2-b]pyridin-7- yl]azetidine-1- sulfonamidecalc'd [M+H]⁺, 440.1; 440.1. 201D

N-[3-(1-methyl-1H- pyrazol-4-yl)-5-oxo- 5H- benzo[4,5]cyclohepta[1,2-b]pyridin-7- yl]azetidine-1- sulfonamide calc'd [M+H]⁺, 422.1;found 422.0. 201E

N-(2-fluoro-3- methoxypropyl)-N- methyl-N′-[3-(1- methyl-1H-pyrazol-4-yl)-5-oxo-5H- benzo[4,5]cyclohepta[1, 2-b]pyridin-7- yl]sulfamide Calc'dfor 486.2 [M+H]+; found 486.2 201F

3-(1-methyl-1H- pyrazol-4-yl)-7-[(2- morpholin-4-yl-2-oxoethyl)amino]-5H- benzo[4,5]cyclohepta [1,2-b]pyridin-5-one Calc'd[M+H]⁺, 430.2; found 430.1

Example 24

N-[3-(4-isopropylpiperazin-1-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide

Method A:

N-(3-chloro-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)methanesulfonamide(0.050 g, 0.15 mmol), isopropylpiperazine (0.038 g, 0.30 mmol),Pd₂(dba)₃ (1.5 mg, 0.0015 mmol), BINAP (3.0 mg, 0.0045 mmol), and sodiumtert-butoxide (0.043 g, 0.45 mmol) were added to a dry flask throughwhich argon was purged. 3.0 mL dry dioxane was added and argon wasbubbled through the solution for 5 minutes. The reaction was stirred andheated to 105° C. After 12 hours, the reaction mixture was poured into100 mL ethyl acetate, 100 mL water, and 25 mL saturated ammoniumchloride. The organic layer was separated, dried with magnesium sulfate,filtered, concentrated, and purified by reverse phase HPLC (20-100%acetonitrile/water gradient, 0.1% trifluoroacetic acid modifier) toafford the title compound.

Method B:

N-(3-chloro-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)methanesulfonamide(0.100 g, 0.30 mmol), Pd₂(dba)₃ (6 mg, 0.006 mmol), rac-BINAP (11 mg,0.018 mmol), and cesium carbonate (0.490 g, 1.50 mmol) combined mixed ina dry tube. Isopropylpiperazine (0.170 mL, 1,20 mmol) and 0.70 mL of drydimethylformamide were added and the tube was sealed. The reactioncontents were heated in the Biotage Initiator series microwave at 180°C. for 15 minutes. The reaction contents were partially concentrated andpurified by reverse phase HPLC (10-100% acetonitrile/water gradient,0.1% trifluoroacetic acid modifier) to afford the title compound.

¹H NMR (600 MHz, CD₃OD) δ 8.64 (d, 1H); 8.18 (s, 1H); 7.96 (d, 1H); 7.68(d, 1H); 7.60 (dd, 1H); 7.20 (d, 1H); 7.18 (d, 1H); 3.45 (m, 4H); 3.04(s, 3H); 2.78 (m, 5H); 1.14 (d, 6H). LRMS (APCI) calculated forC₂₂H₂₇N₄O₃S [M+H]+, 427.2; found 427.2.

The following compounds were made according to Scheme 5. Additionalsynthetic modifications were employed in the preparation of some of thecompounds. Compound 225 and 226 were isolated from a single reactionattempt to prepare the 5-oxo derivative of Compound 225. Compound 230was prepared by N-tert-butoxycarbonyl hydrolysis of Compound 218.Compounds 249 and 250 were prepared from Compounds 236A and 236respectively in a manner similar to that described for Example 4, MethodB. TABLE 4 Comp. # Structure Name MS (M + 1) 203

3-(4-isopropylpiperazin-1-yl)-7- phenyl-5H- benzo[4,5]cyclohepta[1,2-b]pyridin-5-one calc'd 410.2 (M + H)+; found 410.2 (M + H)+ 204

N-(5-oxo-3-piperidin-1-yl-5H- benzo[4,5]cyclohepta[1,2- b]pyridin-7-yl)methanesulfonamide calc'd 384.1 (M + H)+; found 384.1 (M + H)+ 205

N-(3-morpholin-4-yl-5-oxo-5H- benzo[4,5]cyclohepta[1,2- b]pyridin-7-yl)methanesulfonamide calc'd 386.1 (M + H)+; found 386.1 (M + H)+ 206

N-(5-oxo-3-pyrrolidin-1-yl-5H- benzo[4,5]cyclohepta[1,2- b]pyridin-7-yl)methanesulfonamide calc'd 370.1 (M + H)+; found 370.1 (M + H)+ 207

N-[3-(benzylamino)-5-oxo-5H- benzo[4,5]cyclohepta[1,2- b]pyridin-7-yl]methanesulfonamide calc'd 406.1 (M + H)+; found 406.1 (M + H)+ 208

N-{3-[(2,4- dimethoxybenzyl)amino]-5-oxo- 5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7- yl}methanesulfonamide calc'd 466.1 (M + H)+; found 466.1(M + H)+ 209

N-{3-[butyl(methyl)amino]-5- oxo-5H- benzo[4,5]cyclohepta[1,2-b]pyridin-7- yl}methanesulfonamide calc'd 386.2 (M + H)+; found 386.2(M + H)+ 210

N-{3- [(cyclopropylmethyl)amino]-5- oxo-5H- benzo[4,5]cyclohepta[1,2-b]pyridin-7- yl}methanesulfonamide calc'd 370.1 (M + H)+; found 370.1(M + H)+ 211

N-(3-amino-5-oxo-5H- benzo[4,5]cyclohepta[1,2- b]pyridin-7-yl)methanesulfonamide calc'd 316.1 (M + H)+; found 316.1 (M + H)+ 212

N,N′-(5-oxo-5H- benzo[4,5]cyclohepta[1,2- b]pyridine-3,7-diyl)dimethanesulfonamide calc'd 394.1 (M + H)+; found 394.0 (M + H)+213

N-(3-anilino-5-oxo-5H- benzo[4,5]cyclohepta[1,2- b]pyridin-7-yl)methanesulfonamide calc'd 392.1 (M + H)+; found 392.1 (M + H)+ 214

N-[3-(cyclohexylamino)-5-oxo- 5H-benzo[4,5]cyclohepta[1,2- b]pyridin-7-yl]methanesulfonamide calc'd 398.2 (M + H)+; found 398.2 (M + H)+ 215

N-[5-oxo-3-(pyridin-4-ylamino)- 5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7- yl]methanesulfonamide calc'd 393.1 (M + H)+; found 393.1(M + H)+ 216

N-[5-oxo-3-(pyridin-3-ylamino)- 5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7- yl]methanesulfonamide calc'd 393.1 (M + H)+; found 393.1(M + H)+ 217

N-[5-oxo-3-(pyridin-2-ylamino)- 5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7- yl]methanesulfonamide calc'd 393.1 (M + H)+; found 392.7(M + H)+ 218

tert-butyl 4-{7- [(methylsulfonyl)amino]-5-oxo-5H-benzo[4,5]cyclohepta[1,2- b]pyridin-3-yl}piperazine-1- carboxylatecalc'd 485.2 (M + H)+; found 485.2 (M + H)+ 219

N-[3-(4-methylpiperazin-1-yl)-5- oxo-5H- benzo[4,5]cyclohepta[1,2-b]pyridin-7- yl]methanesulfonamide calc'd 399.1 (M + H)+; found 399.1(M + H)+ 220

N-[3-(1,4-dioxa-8- azaspiro[4.5]dec-8-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2- b]pyridin-7- yl]methanesulfonamide calc'd442.1 (M + H)+; found 442.2 (M + H)+ 221

N-[5-oxo-3-(4-quinolin-2- ylpiperazin-1-yl)-5H-benzo[4,5]cyclohepta[1,2- b]pyridin-7- yl]methanesulfonamide calc'd512.2 (M + H)+; found 512.2 (M + H)+ 222

N-{3-[(4-chlorobenzyl)amino]- 5-oxo-5H- benzo[4,5]cyclohepta[1,2-b]pyridin-7- yl}methanesulfonamide calc'd 440.1 (M + H)+; found 440.1(M + H)+ 223

N-{5-oxo-3-[(1- phenylethyl)amino]-5H- benzo[4,5]cyclohepta[1,2-b]pyridin-7- yl}methanesulfonamide calc'd 420.1 (M + H)+; found 420.2(M + H)+ 224

N-{3-[(2-morpholin-4- ylethyl)amino]-5-oxo-5H- benzo[4,5]cyclohepta[1,2-b]pyridin-7- yl}methanesulfonamide calc'd 429.2 (M + H)+; found 429.2(M + H)+ 225

N-{5-hydroxy-3-[3- (trifluoromethyl)-5,6- dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-5H- benzo[4,5]cyclohepta[1,2- b]pyridin-7-yl}methanesulfonamide calc'd 493.1 (M + H)+; found 493.2 (M + H)+ 226

N-(3-chloro-5-hydroxy-5H- benzo[4,5]cyclohepta[1,2- b]pyridin-7-yl)methanesulfonamide calc'd 337.0 (M + H)+; found 337.1 (M + H)+ 227

N-(3-{4-[(2-methyl-1,3-thiazol- 4-yl)methyl]piperazin-1-yl}-5- oxo-5H-benzo[4,5]cyclohepta[1,2- b]pyridin-7- yl)methanesulfonamide calc'd496.1 (M + H)+; found 496.2 (M + H)+ 228

N-{3-[4-(4-chloropyridin-2- yl)piperazin-1-yl]-5-oxo-5H-benzo[4,5]cyclohepta[1,2- b]pyridin-7- yl}methanesulfonamide calc'd496.1 (M + H)+; found 496.1 (M + H)+ 229

N-{5-oxo-3-[4-(pyridin-3- ylmethyl)piperazin-1-yl]-5H-benzo[4,5]cyclohepta[1,2- b]pyridin-7- yl}methanesulfonamide calc'd476.2 (M + H)+; found 476.2 (M + H)+ 230

N-(5-oxo-3-piperazin-1-yl-5H- benzo[4,5]cyclohepta[1,2- b]pyridin-7-yl)methanesulfonamide calc'd 385.1 (M + H)+; found 385.2 (M + H)+ 231

N-{5-oxo-3-[4-(pyridin-2- ylmethyl)piperazin-1-yl]-5H-benzo[4,5]cyclohepta[1,2- b]pyridin-7- yl}methanesulfonamide calc'd476.2 (M + H)+; found 476.2 (M + H)+ 232

N-[5-oxo-3-(4-pyridin-3- ylpiperazin-1-yl)-5H- benzo[4,5]cyclohepta[1,2-b]pyridin-7- yl]methanesulfonamide calc'd 462.2 (M + H)+; found 462.2(M + H)+ 233

N-{5-oxo-3-[2-(trifluoromethyl)- 5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl]-5H- benzo[4,5]cyclohepta[1,2- b]pyridin-7-yl}methanesulfonamide calc'd 490.1 (M + H)+; found 490.1 (M + H)+ 234

N-(3-{4-[3,5- bis(trifluoromethyl)phenyl]piper- azin-1-yl}-5-oxo-5H-benzo[4,5]cyclohepta[1,2- b]pyridin-7- yl)methanesulfonamide calc'd597.1 (M + H)+; found 597.1 (M + H)+ 235

N-{3-[(1-methyl-1H-pyrazol-3- yl)amino]-5-oxo-5H-benzo[4,5]cyclohepta[1,2- b]pyridin-7- yl}methanesulfonamide calc'd396.1 (M + H)+; found 395.7 (M + H)+ 236

7-[(2,4- dimethoxybenzyl)amino]-3-(1,4- dioxa-8-azaspiro[4.5]dec-8-yl)-5H-benzo[4,5]cyclohepta[1,2- b]pyridin-5-one calc'd 514.2 (M + H)+;found 514.3 (M + H)+ 236A

7-[(2,4- dimethoxybenzyl)amino]-3- (4-isopropylpiperazin-1-yl)-5H-benzo[4,5]cyclohepta[1,2- b]pyridin-5-one calc'd 499.3 (M + H)+;found 499.3 (M + H)+ 237

3-(4-isopropylpiperazin-1-yl)-7- morpholin-4-yl-5H-benzo[4,5]cyclohepta[1,2- b]pyridin-5-one calc'd 419.2 (M + H)+; found419.2 (M + H)+ 238

3-(4-acetylpiperazin-1-yl)-7- morpholin-4-yl-5H-benzo[4,5]cyclohepta[1,2- b]pyridin-5-one calc'd 419.2 (M + H)+; found419.2 (M + H)+ 239

3-(4-isopropylpiperazin-1-yl)-7- [(1-phenylethyl)amino]-5H-benzo[4,5]cyclohepta[1,2- b]pyridin-5-one calc'd 453.2 (M + H)+; found452.8 (M + H)+ 240

7-anilino-3-(4- isopropylpiperazin-1-yl)-5H- benzo[4,5]cyclohepta[1,2-b]pyridin-5-one calc'd 425.2 (M + H)+; found 425.2 (M + H)+ 241

7-(benzylamino)-3-(4- isopropylpiperazin-1-yl)-5H-benzo[4,5]cyclohepta[1,2- b]pyridin-5-one calc'd 439.2 (M + H)+; found439.2 (M + H)+ 242

4-[7-(benzylamino)-5-oxo-5H- benzo[4,5]cyclohepta[1,2-b]pyridin-3-yl]-N,N- dimethylpiperazine-1- carboxamide calc'd 468.2 (M +H)+; found 468.2 (M + H)+ 243

7-(tert-butylamino)-3-(4- isopropylpiperazin-1-yl)-5H-benzo[4,5]cyclohepta[1,2- b]pyridin-5-one calc'd 405.3 (M + H)+; found404.8 (M + H)+ 244

3-(4-isopropylpiperazin-1-yl)-7- [(2-methoxyethyl)amino]-5H-benzo[4,5]cyclohepta[1,2- b]pyridin-5-one calc'd 407.2 (M + H)+; found407.2 (M + H)+ 245

3-(4-isopropylpiperazin-1-yl)-7- [(3-methoxypropyl)amino]-5H-benzo[4,5]cyclohepta[1,2- b]pyridin-5-one calc'd 421.3 (M + H)+; found421.3 (M + H)+ 246

7-[(1-ethylpropyl)amino]-3-(4- isopropylpiperazin-1-yl)-5H-benzo[4,5]cyclohepta[1,2- b]pyridin-5-one calc'd 419.3 (M + H)+; found419.3 (M + H)+ 247

7-[(1-ethylpropyl)amino]-3-(4- methyl-1,4-diazepan-1-yl)-5H-benzo[4,5]cyclohepta[1,2- b]pyridin-5-one calc'd 405.3 (M + H)+; found405.2 (M + H)+ 248

7-[(3-methoxypropyl)amino]-3- (4-methyl-1,4-diazepan-1-yl)-5H-benzo[4,5]cyclohepta[1,2- b]pyridin-5-one calc'd 407.2 (M + H)+;found 407.2 (M + H)+ 249

7-amino-3-(4- isopropylpiperazin-1-yl)-5H- benzo[4,5]cyclohepta[1,2-b]pyridin-5-one calc'd 349.2 (M + H)+; found 349.2 (M + H)+ 250

7-amino-3-(4-oxopiperidin-1- yl)-5H- benzo[4,5]cyclohepta[1,2-b]pyridin-5-one calc'd 320.1 (M + H)+; found 320.1 (M + H)+ 251

7-hydroxy-3-(4- isopropylpiperazin-1-yl)-5H- benzo[4,5]cyclohepta[1,2-b]pyridin-5-one calc'd 350.2 (M + H)+; found 350.1 (M + H)+ 252

3-(4-isopropylpiperazin-1-yl)- 7-piperidin-1-yl-5H-benzo[4,5]cyclohepta[1,2- b]pyridin-5-one calc'd 417.2 (M + H)+; found417.3 (M 253

3,7-bis{[(3-methylpyridin-4- yl)methyl]amino}-5H-benzo[4,5]cyclohepta[1,2- b]pyridin-5-one calc'd 448.2 (M + H)+; found448.2 (M

Example 25

N-(3-chloro-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)-2-methoxyacetamide

7-amino-3-chloro-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one (0.70 g,2.7 mmol) was dissolved in 20 mL of dry dichloromethane and 5 mL of dryacetonitrile. Methoxyacetic acid (0.32 mL, 4.1 mmol),N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDCI)(0.79 g, 4.1 mmol) and 1-hydroxybenzotriazole hydrate (HOBt) (0.55 g,4.1 mmol) were added and the solution was stirred at ambienttemperature. After 12 hours, the reaction solution was poured into 300mL of ethyl acetate and 100 mL of water. The organic layer was separatedand washed with 100 mL of brine. The organic layer was separated, driedwith magnesium sulfate, filtered, concentrated and purified by flashcolumn chromatography (0-100% ethyl acetate/hexanes gradient) to affordthe title compound. ¹H NMR (600 MHz, CDCl₃) δ 10.29 (s, 1H); 8.94 (d,1H); 8.58 (d, 1H); 8.46 (d, 1H); 8.10 (dd, 1H); 7.77 (d, 1H); 7.40 (d,1H); 7.20 (d, 1H); 4.04 (s, 2H); 3.36 (s, 3H). LRMS (APCI) calculatedfor C₁₇H₁₄ClN₂O₃ [M+H]+, 329.1; found 329.1.

Example 26

ethyl(5-oxo-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-8-yl)carbamate

To a 0° C. solution of8-amino-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one (6.4 mg,0.021 mmol) in pyridine (0.3 mL) was added a catalytic amount of4-dimethylaminopyridine (tip of the spatula) and ethyl chloroformate(0.1 mL, 0.31 M in CH₂Cl₂) The mixture was then stirred at roomtemperature. After 7 hours, more ethyl chloroformate (3 μL, 0.032 mmol)was added. After stirring for 14 hours, a new addition of ethylchloroformate (6 μL, 0.064 mmol) was followed by stirring for 2 morehours.

The mixture was then concentrated to dryness. The crude residue waspurified by flash chromatography (100-85% CH₂Cl₂₁MeOH gradient). Thecollected fractions were concentrated, dissolved in CH₂Cl₂ washed withan aqueous saturated solution of CuSO₄, brine, dried over sodiumsulfate, filtered, and concentrated to afford the title compound. ¹H NMR(600 MHz, CDCl₃) δ 9.12 (s, 1H), 8.85 (s, 1H), 8.31 (d, 1H), 7.78 (s,1H), 7.71 (d, 2H), 7.53 (m, 3H), 7.45 (t, 2H), 6.97 (s, 1H), 4.27 (q,2H), 1.34 (t, 3H). LRMS (APCI) calculated for C₂₃H₁₉N₂O₃ [M+H]+, 372.1;found 372.1

Example 27

N-ethyl-N′-(5-oxo-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-8-yl)urea

To a 0° C. solution of8-amino-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one (6.4 mg,0.021 mmol) in pyridine (0.3 mL) was ethyl isocyanate (0.1 mL, 0.38 M inCH₂Cl₂) The mixture was then stirred at room temperature for 4 hoursfollowed by heating at 50° C. After 3 hours, more ethyl isocianate (3μL, 0.038 mmol) was added and the mixture was heated at 70° C. Afterstirring for 14 hours, a new addition of ethyl isocyanate (9 μL, 0.114mmol) was followed by heating at 80° C. More ethyl isocyanate (20 μL,0.253 mmol) was added 2 hours later and heating was continued for 14hours. The mixture was then concentrated to dryness. The crude residuewas purified by flash chromatography (100-85% CH₂Cl₂/MeOH gradient) andreverse phase HPLC (30-100% acetonitrile/water gradient, 0.1%trifluoroacetic acid modifier) to afford the title compound. ¹H NMR (600MHz, DMSO-D₆) δ 9.24 (d, 1H), 8.69 (d, 1H), 8.14 (d, 1H), 7.85 (d, 2H),7.80 (d, 1H), 7.67 (dd, 1H), 7.53 (t, 2H), 7.45 (t, 2H), 7.31 (s, 2H),2.95 (m, 2H), 0.93 (t, 3H). LRMS (APCI) calculated for C₂₃H₂₀N₃O₂[M+H]+, 370.1; found 370.1

Example 28

N-(2,4-dimethoxybenzyl)-N-(5-oxo-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)ethylenesulfonamide

A flask was charged with compound 19 (194 mg, 0.434 mmol) and 8 mL ofCH₂Cl₂ and cooled to 0° C. N-methylmorpholine (0.19 mL, 1.74 mmol) and2-chloroethanesulfonyl chloride (90 μL, 0.87 mmol) were added and thesolution was allowed to warm to room temperature. After 18 h, thesolution was diluted with EtOAc, washed with water and brine, then driedover Na₂SO₄. The solution was concentrated in vacuo and purified byflash column chromatography (10-100% EtOAc/hexanes gradient) to affordthe title compound 257. ¹H NMR (600 MHz, CDCl₃) δ 9.14 (d, 1H); 8.73 (d,1H); 8.19 (d, 1H); 7.69-7.72 (m, 2H); 7.58 (dd, 1H); 7.49-7.54 (m, 3H);7.44-7.47 (m, 1H); 7.39 (d, 1H); 7.19-7.25 (m, 2H); 6.57 (dd, 1H); 6.37(dd, 1H); 6.30 (app d, 1H); 6.21 (d, 1H); 6.00 (d, 1H); 4.86 (s, 2H);3.72 (s, 3H); 3.65 (s, 3H). LRMS (APCI) calc'd for (C₃₁H₂₇N₂O₅S) [M+H]+,539.2; found 539.2

Example 29

N-(5-oxo-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)ethylenesulfonamide

Compound 258 was prepared from 257 via the method described for Example4B. ¹H NMR (600 MHz, DMSO-d₆) δ 10.69 (s, 1H); 9.29 (257, 1H); 8.68 (d,1H); 7.98 (d, 1H); 7.86-7.90 (m, 2H); 7.78 (d, 1H); 7.52-7.58 (m, 3H);7.45-7.48 (m, 1H); 7.41 (d, 1H); 7.29 (d, 1H); 6.86 (dd, 1H); 6.20 (d,1H); 6.06-6.10 (m, 1H). LRMS (APCI) calc'd for (C₂₂H₁₇N₂O₃S) [M+H]+,389.1; found 389.1

Example 30

N-(5-oxo-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)-2-pyrrolidin-1-ylethanesulfonamide

Compound 258 (20.0 mg, 0.051 mmol) and pyrrolidine (13 μL, 0.15 mmol)were dissolved in 2 mL of MeOH and 1 mL of CH₂Cl₂. After 18 h, thesolution was concentrated under a stream of nitrogen and purified bypurified by reverse phase HPLC (20-100% CH₃CN/water with a 0.1% TFAmodifier) to afford the title compound 259. ¹H NMR (600 MHz, CDCl₃) δ9.13 (d, 1H); 8.74 (d, 1H); 7.92 (d, 1H); 7.73 (dd, 1H); 7.68-7.73 (m,2H); 7.58 (d, 1H); 7.49-7.53 (m, 2H); 7.42-7.45 (m, 1H); 7.36 (d, 1H);7.23 (d, 1H); 3.28-3.32 (m, 2H); 3.08-3.12 (m, 2H); 2.60-2.65 (m, 4H);1.88-1.94 (m, 4H). LRMS (APCI) calc'd for (C₂₆H₂₆N₃O₃S) [M+H]+, 460.2;found 460.

Example 31

N-methyl-N-(5-oxo-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)methanesulfonamide

Compound 44 (5.0 mg, 0.013 mmol) was dissolved in 0.5 mL of MeOH and 1mL of CH₂Cl₂, then trimethylsilyldiazomethane (14 μL of a 2M solution inCH₂Cl₂, 0.03 mmol) was added. After 30 min, additionaltrimethylsilyldiazomethane (14 μL of a 2M solution in CH₂Cl₂, 0.03 mmol)was added. After an additional 30 min, the solution was concentrated invacuo to afford the title compound 260. ¹H NMR (600 MHz, CDCl₃) δ 9.10(d, 1H); 8.69 (d, 1H); 8.16 (d, 1H); 7.77 (dd, 1H); 7.64-7.67 (m, 2H);7.59 (d, 1H); 7.45-7.49 (m, 2H); 7.37-7.42 (m, 2H); 7.23 (d, 1H); 3.39(s, 3H); 2.84 (s, 3H). LRMS (APCI) calc'd for (C₂₂H₁₉N₂O₃S) [M+H]+,391.1; found 391.1

Example 32

3-chloro-7-[(2,4-dimethoxybenzyl)(methyl)amino]-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one

Compound 7 (100.0 mg, 0.246 mmol), paraformaldehyde (24 mg, 0.27 mmol),and NaBH(OAc)₃ (57 mg, 0.27 mmol) were suspended in 4 mL ofdichloroethane and 2 mL of dioxane and stirred overnight. After 18 h,additional paraformaldehyde (122 mg, 1.35 mmol), NaBH(OAc)₃ (172 mg,0.81 mmol) and 5 mL of dioxane were added and the mixture was heated to60° C. After 24 h, additional paraformaldehyde (222 mg, 2.46 mmol) andNaBH(OAc)₃ (521 mg, 2.46 mmol) were added. After an additional 24 h.,the mixture was diluted in EtOAc, washed with water and brine, thendried over Na₂SO₄. The solution was concentrated in vacuo and purifiedby flash column chromatography (10-100% EtOAc/hexanes gradient) toafford the title compound 261. ¹H NMR (600 MHz, CDCl₃) δ 8.75 (d, 1H);8.56 (d, 1H); 7.65 (d, 1H); 7.43 (d, 1H); 7.18 (d, 1H); 7.09 (d, 1H);7.03 (dd, 1H); 6.89 (d, 1H); 6.49 (d, 1H); 6.36 (dd, 1H); 4.58 (s, 2H);3.84 (s, 3H); 3.76 (s, 3H); 3.17 (s, 3H). LRMS (APCI) calc'd for(C₂₄H₂₂ClN₂O₃) [M+H]+, 421.1; found 420.7.

Example 33

dimethyl[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]amidophosphate.(Compound 262)

Compound 139 (10 mg, 0.033 mmol) and triethylamine (14 μL, 0.10 mmol)was suspended in 2 mL dichloromethane and dimethyl chloridophosphate (7μL, 0.066 mmol) was added. After 30 min, the suspension was heated to40° C. After an additional 2 h, dimethyl chloridophosphate (36 μL, 0.33mmol) was added. After an additional 18 h the yellow solution was pouredinto ethylacetate and the organic layer was washed with saturatedaqueous sodium bicarbonate and brine, then dried over sodium sulfate andconcentrated. The residue was purified via reverse phase HPLC (20-100%acetonitrile/water gradient, 0.05% trifluoroacetic acid modifier) toafford the title compound. ¹H NMR (600 MHz, CDCl₃) δ 8.89 (d, 1H); 8.63(s, 1H); 7.88 (s, 1H); 7.82 (d, 1H); 7.79 (s, 1H); 7.51 (d, 1H);7.32-7.38 (m, 2H); 7.18-7.22 (m, 1H); 6.06 (br d, 1H); 3.94 (s, 3H);3.79(s, 3H); 3.77 (s, 3H); LRMS (APCI) calc'd for (C₂OH-2N₄O₄P) [M+H]+,411.1; found 411.1.

The following compounds were made according to Scheme 6. Additionalsynthetic modifications were employed in the preparation of some of thecompounds. Compounds 263 and 264 were isolated during the formation ofCompounds 44 and 265 using the procedure described in Example 5, MethodB. Compound 268 was isolated from the reaction mixture in preparation ofCompound 267. Compound 271 was prepared by acylation of Compound 23 withacetyl chloride. Compound 275 was prepared by condensation of Compound 8with phtalic anhydride. Compound 278 was isolated from the coupling ofCompound 254 to 1,4-dioxa-8-azaspiro[4,5]decane in a manner to thatdescribed in Example 24, Method B. Compounds 281, 286, and 287 wereprepared in a manner similar to that described for Compound 259 with DMFused as a co-solvent. Compound 285 was isolated from the reactionmixture in the preparation of Compound 286. Compound 288 was preparedfrom the coupling of Compound 287 to 1,4-dioxa-8-azaspiro[4,5]decane ina manner similar to that described in Example 24. Compound 289 wasprepared from Compound 261 respectively in a manner similar to thatdescribed for Example 4, Method B. TABLE 5 Compound Structure Name MS(M + 1) 263

N,N-(5-oxo-3-phenyl-5H- benzo[4,5]cyclohepta[1,2- b]pyridin-7-yl)bis-methanesulfonamide calc'd 455.1 (M + H+); found 455.1 (M + H)+ 264

N,N-(5-oxo-3-phenyl-5H- benzo[4,5]cyclohepta[1,2- b]pyridin-7-yl)bis-benzenesulfonamide calc'd 579.1 (M + H+); found 579.1 (M + H)+ 265

N-(5-oxo-3-phenyl-5H- benzo[4,5]cyclohepta[1,2- b]pyridin-7-yl)benzenesulfonamide calc'd 439.1 (M + H+); found 439.1 (M + H)+ 266

N-(5-oxo-3-phenyl-5H- benzo[4,5]cyclohepta[1,2- b]pyridin-7-yl)ethanesulfonamide calc'd 391.1 (M + H+); found 391.1 (M + H)+ 267

N-[3-(1-methyl-1H-pyrazol- 4-yl)-5-oxo-5H- benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]propane-2- sulfonamide calc'd 409.1 (M + H+); found 408.7(M + H)+ 268

2-chloro-N-[3-(1-methyl- 1H-pyrazol-4-yl)-5-oxo- 5H-benzo[4,5]cyclohepta[1,2- b]pyridin-7-yl]propane-2- sulfinamide calc'd427.1 (M + H+); found 426.7 (M + H)+ 269

N-(5-oxo-3-phenyl-5H- benzo[4,5]cyclohepta[1,2- b]pyridin-7-yl)-2-phenylacetamide calc'd 417.2 (M + H+); found 417.2 (M + H)+ 270

2-methoxy-N-(5-oxo-3- phenyl-5H- benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)acetamide calc'd 371.1 (M + H+); found 371.1 (M + H)+ 271

N-acetyl-N′-(5-oxo-3- phenyl-5H- benzo[4,5]cyclohepta[1,2-b]pyridin-9-yl)acetamide calc'd 442.1 (M + H+); found (M + H)+ 272

N-[3-(4-isopropylpiperazin- 1-yl)-5-oxo-5H- benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-2- methoxyacetamide calc'd 421.2 (M + H+); found 421.3(M + H)+ 273

N-[3-(1,4-dioxa-8- azaspiro[4.5]dec-8-yl)-5- oxo-5H-benzo[4,5]cyclohepta[1,2- b]pyridin-7-yl]-2- methoxyacetamide calc'd436.2 (M + H+); found 436.2 (M + H)+ 274

2-methoxy-N-[5-oxo-3-(3- thienyl)-5H- benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]acetamide calc'd 377.1 (M + H+); found 377.1 (M + H)+ 275

2-{[(3-chloro-5-oxo-5H- benzo[4,5]cyclohepta[1,2- b]pyridin-7-yl)amino]carbonyl}benzoic acid calc'd 404.1 (M + H+); found 405.1 (M +H)+ 276

ethyl [3-(1-methyl-1H- pyrazol-4-yl)-5-oxo-5H- benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]carbamate calc'd 375.1 (M + H+); found 375.1 (M + H)+ 277

N-ethyl-N′-[3-(1-methyl- 1H-pyrazol-4-yl)-5-oxo- 5H-benzo[4,5]cyclohepta[1,2- b]pyridin-7-yl]urea calc'd 374.2 (M + H+);found 374.2 (M + H)+ 278

7-amino-3-(1,4-dioxa-8- azaspiro[4.5]dec-8-yl)-5H-benzo[4,5]cyclohepta[1,2- b]pyridin-5-one calc'd 364.2 (M + H+); found364.2 (M + H)+ 279

2-(diethylamino)-N-(5-oxo- 3-phenyl-5H- benzo[4,5]cyclohepta[1,2-b]pyridin-7- yl)ethanesulfonamide calc'd 462.2 (M + H+); found 462.2(M + H)+ 280

2-morpholin-4-yl-N-(5-oxo- 3-phenyl-5H- benzo[4,5]cyclohepta[1,2-b]pyridin-7- yl)ethanesulfonamide calc'd 476.2 (M + H+); found 476.2(M + H)+ 281

2-(1H-imidazol-1-yl)-N-(5- oxo-3-phenyl-5H- benzo[4,5]cyclohepta[1,2-b]pyridin-7- yl)ethanesulfonamide calc'd 457.1 (M + H+); found 457.2(M + H)+ 282

2-[(2,4- dimethoxybenzyl)amino]- N-(5-oxo-3-phenyl-5H-benzo[4,5]cyclohepta[1,2- b]pyridin-7- yl)ethanesulfonamide calc'd 556.2(M + H+); found 556.2 (M + H)+ 283

2-[(2-morpholin-4- ylethyl)amino]-N-(5-oxo-3- phenyl-5H-benzo[4,5]cyclohepta[1,2- b]pyridin-7- yl)ethanesulfonamide calc'd 519.2(M + H+); found 519.2 (M + H)+ 284

2-(benzylamino)-N-(5-oxo- 3-phenyl-5H- benzo[4,5]cyclohepta[1,2-b]pyridin-7- yl)ethanesulfonamide calc'd 496.2 (M + H+); found 496.2(M + H)+ 285

2-(dimethylamino)-N-(5- oxo-3-phenyl-5H- benzo[4,5]cyclohepta[1,2-b]pyridin-7- yl)ethanesulfonamide calc'd 434.2 (M + H+); found 434.2(M + H)+ 286

N-(5-oxo-3-phenyl-5H- benzo[4,5]cyclohepta[1,2- b]pyridin-7-yl)-2-(1H-pyrazol-1- yl)ethanesulfonamide calc'd 457.1 (M + H+); found 457.1 (M +H)+ 287

N-(3-chloro-5-oxo-5H- benzo[4,5]cyclohepta[1,2- b]pyridin-7-yl)-2-(1H-imidazol-1- yl)ethanesulfonamide calc'd 415.1 (M + H+); found 415.1 (M +H)+ 288

N-[3-(1,4-dioxa-8- azaspiro[4.5]dec-8-yl)-5- oxo-5H-benzo[4,5]cyclohepta[1,2- b]pyridin-7-yl]-2-(1H- imidazol-1-yl)ethanesulfonamide calc'd 522.2 (M + H+); found 522.2 (M + H)+ 289

7-(methylamino)-3-(1- methyl-1H-pyrazol-4-yl)- 5H-benzo[4,5]cyclohepta[1,2- b]pyridin-5-one calc'd 317.1 (M + H+); found316.8 (M + H)+ 290

N-[3-(1-methyl-1H-pyrazol- 4-yl)-5-oxo-5H- benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]sulfamide calc'd 382.1 (M + H+); found 382.1 (M + H)+ 291

tert-butyl ({[3-(1-methyl-1H- pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2- b]pyridin-7- yl]amino}sulfonyl)carbamatecalc'd 482.1 (M + H+); found 482.2 (M + H)+

Example 34

N-(5-hydroxy-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)methanesulfonamide

To a stirred slurry ofN-(5-oxo-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)methanesulfonamide(0.50 g, 1.3 mmol) in MeOH (30 mL) was added NaBH₄ (100 mg, 2.6 mmol).The reaction mixture was left to stir for 30 min, treated with 1 N HCland then 1 N NaOH, and concentrated. The residue was diluted with EtOAcand washed with brine. The organic layer was dried (Na₂SO₄),concentrated, and purified by flash chromatography to afford the titlecompound. ¹H NMR (600 MHz, CD₃OD) δ 8.66 (d, 1H); 8.38 (d, 1H);7.15-7.71 (m, 10H); 5.28 (s, 1H); 2.96 (s, 3H). LRMS (APCI) calc'd for(C₂₁H₁₉N₂O₃S) [M+H]+, 379.1; found 379.1.

Example 35

7-[(methylsulfonyl)amino]-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-ylacetate

To a stirred solution ofN-(5-hydroxy-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)methanesulfonamide(50 mg, 0.13 mmol) in AcOH (1 mL) was added Ac₂O (0.5 mL). The reactionmixture was heated to 120° C. for 1 d, concentrated, and purified byflash chromatography to afford the title compound. ¹H NMR (600 MHz,CDCl₃) δ 8.83 (s, 1H); 8.11 (s, 1H); 7.18-7.63 (m, 10H); 6.75 (s, 1H);3.03 (s, 3H); 2.23 (br s, 3H). LRMS (APCI) calc'd for (C₂₃H₂₁N₂O₄S)[M+H]+, 421.1; found 421.1.

Example 36

N-(5-methoxy-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)-N-methylmethanesulfonamide

To a stirred solution ofN-(5-hydroxy-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)methanesulfonamide(30 mg, 0.079 mmol) in THF (3 mL) was added NaH (60%, 10 mg, 0.25 mmol)at 0° C. After 10 min, MeI (50 μL, 0.80 mmol) was added, and theresultant mixture was allowed to stir at room temperature for 4 h. Thereaction mixture was treated with water, diluted with EtOAc, washed withbrine, dried (Na₂SO₄), concentrated, and purified by flashchromatography to afford the title compound. ¹H NMR (600 MHz, CDCl₃) δ8.71 (s, 1H); 8.07 (s, 1H); 7.19-7.60 (m, 10H); 4.71 (br s, 1H); 3.50(br s, 3H); 3.28 (s, 3H); 2.79 (s, 3H). LRMS (APCI) calc'd for(C₂₃H₂₃N₂O₃S) [M+H]+, 407.1; found 407.2.

Example 37

N-(3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)methanesulfonamide

Compound 263 (10.0 mg, 0.022 mmol) and Zn dust (14 mg, 0.22 mmol) weresuspended in 2 mL of AcOH and heated to 100° C. After 24 h, the mixturewas filtered though a 0.45μ Nylon syringe filter, concentrated in vacuoand purified by reverse phase HPLC (20-80% CH₃CN/water with a 0.1% TFAmodifier) to affordN,N-(3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)-bis-methanesulfonamide.

N,N-(3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)-bis-methanesulfonamidewas converted to the title compound 295 via the method described in thebasic hydrolysis step of Example 5B. ¹H NMR (600 MHz, CDCl₃) δ 8.68 (s,1H); 7.77 (s, 1H); 7.52-7.55 (m, 2H); 7.40-7.44 (m, 2H); 7.33-7.37 (m,1H); 7.27 (d, 1H); 7.12-7.22 (m, 3H); 7.00 (dd, 1H); 6.57 (s, 1H); 3.74(s, 2H); 2.95 (s, 3H). LRMS (APCI) calc'd for (C₂₁H₁₉N₂O₂S) [M+H]+,363.1; found 363.1.

Example 38

N-[(5E/Z)-5-(hydroxyimino)-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide

To a stirred solution ofN-(5-oxo-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)methanesulfonamide(0.10 g, 0.27 mmol) in EtOH (7 mL) was added hydroxylamine hydrochloride(0.30 g, 4.3 mmol). The reaction mixture was heated to 90° C. for 5 h,cooled to room temperature, concentrated, and purified by flashchromatography to afford the title compound as a 3:2 mixture of theisomers. For the major isomer; ¹H NMR (600 MHz, CD₃OD) δ 8.82 (d, 1H);8.30 (d, 1H); 7.00-7.70 (m, 10H); 3.02 (s, 3H). LRMS (APCI) calc'd for(C₂₁H₁₈N₃O₃S) [M+H]+, 392.1; found 392.1.

Example 39

N-(3-phenyl-5-pyrrolidin-1-yl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)methanesulfonamide

To a stirred solution ofN-(5-hydroxy-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)methanesulfonamide(40 mg, 0.11 mmol) in CH₂Cl₂ (2 mL) was added SOCl₂ (30 uL, 0.41 mmol)at 0° C. The mixture was left to stir at 0° C. for 1 h and concentratedin vacuo. To the residue were added CH₂Cl₂ (2 mL) and pyrroldine (0.10mL, 1.2 mmol) at 0° C. The mixture was allowed to warm to roomtemperature as the bath did, and left to stir overnight. The mixture wasconcentrated and purified by flash chromatography to afford the titlecompound. ¹H NMR (600 MHz, CD₃OD) δ 8.83 (s, 1H); 7.91 (s, 1H);7.15-7.64 (m, 10H); 4.31 (br s, 1H); 3.02 (s, 3H); 2.09 (br s, 4H); 1.61(br s, 4H). LRMS (APCI) calc'd for (C₂₅H₂₆N₃O₂S) [M+H]+, 432.2; found432.1.

The following compounds were made according to Scheme 7. TABLE 6Compound Structure Name MS (M + 1) 298

N-[(5E/Z)-5- (methoxyimino)-3- phenyl-5H- benzo[4,5]cyclohepta[1,2-b]pyridin-7- yl]methanesulfonamide calc'd 406.1 (M + H+); found 406.1(M + H)+ 299

N-[(5E/Z)-5-(tert- butoxyimino)-3-phenyl- 5H- benzo[4,5]cyclohepta[1,2-b]pyridin-7- yl]methanesulfonamide calc'd 448.2 (M + H+); found 448.2(M + H)+ 300

(5E/Z)-7-amino-3-phenyl- 5H- benzo[4,5]cyclohepta[1,2- b]pyridin-5-oneoxime calc'd 314.1 (M + H+); found 314.2 (M + H)+ 301

N-[5-(dimethylamino)-3- phenyl-5H- benzo[4,5]cyclohepta[1,2-b]pyridin-7- yl]methanesulfonamide calc'd 406.2 (M + H+); found 406.1(M + H)+ 302

N-[5-(isopropylamino)-3- phenyl-5H- benzo[4,5]cyclohepta[1,2-b]pyridin-7- yl]methanesulfonamide calc'd 420.2 (M + H+); found 420.1(M + H)+ 303

N-[5-(cyclopropylamino)- 3-phenyl-5H- benzo[4,5]cyclohepta[1,2-b]pyridin-7- yl]methanesulfonamide calc'd 418.2 (M + H+); found 418.1(M + H)+ 304

N-[5-(benzylamino)-3- phenyl-5H- benzo[4,5]cyclohepta[1,2- b]pyridin-7-yl]methanesulfonamide calc'd 468.2 (M + H+); found 468.1 (M + H)+ 305

N-(5-azetidin-1-yl-3- phenyl-5H- benzo[4,5]cyclohepta[1,2- b]pyridin-7-yl)methanesulfonamide calc'd 418.2 (M + H+); found 418.1 (M + H)+ 306

N-(3-phenyl-5-piperidin- 1-yl-5H- benzo[4,5]cyclohepta[1,2- b]pyridin-7-yl)methanesulfonamide calc'd 446.2 (M + H+); found 446.1 (M + H)+ 307

N-(5-morpholin-4-yl-3- phenyl-5H- benzo[4,5]cyclohepta[1,2- b]pyridin-7-yl)methanesulfonamide calc'd 448.2 (M + H+); found 448.1 (M + H)+ 308

7- [(methylsulfonyl)amino]- 3-phenyl-5- piperazinediium-1-yl-5H-benzo[4,5]cyclohepta[1,2- b]pyridine calc'd 447.2 (M + H+); found 447.2(M + H)+

Example 40

7-(hydroxymethyl)-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-ol

LiAlH₄ (22 mg, 0.586 mmol) was added to a solution of Compound 12 (100.0mg, 0.293 mmol) in 3 mL of THF. After 1 h, the reaction was quenched bythe addition of 22 μL of water. After 30 min, 66 μL of 2.5 M NaOH wasadded and after 30 min an additional 22 μL of water was added and themixture was stirred vigorously. After 18 h, the mixture was filtered andthe solid was washed successively with EtOAc (100 mL) and a 1:1MeOH/CH₂Cl₂ (50 mL) solution. The filtrate was concentrated in vacuo toafford the crude diol 309. LRMS (APCI) calc'd for (C₂₁H₁₈NO₂) [M+H]+,316.1; found 316.2.

Example 40A

7-({[tert-butyl(dimethyl)silyl]oxy}methyl)-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-ol

Diol 309 (90 mg, 0.285 mmol), imidazole (49 mg, 0.71 mmol) andtert-butyldimethylsilylchloride (0.31 mmol, 48 mg) were dissolved in 3mL of DMF. After 1 h, an additional 2 mL of DMF were added. After 1 h,additional imidazole (49 mg, 0.71 mmol) andtert-butyldimethylsilylchloride (0.31 mmol, 48 mg) were added. After afurther 18 h, the mixture was poured into EtOAc, washed with water andbrine, then dried over Na₂SO₄ and concentrated in vacuo to afford thecrude alcohol 310. LRMS (APCI) calc'd for (C₂₇H₃₂NO₂Si) [M+H]+, 430.2;found 430.2.

Example 41

7-({[tert-butyl(dimethyl)silyl]oxy}methyl)-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one

Manganese dioxide (250 mg, 2.88 mmol) was added to a solution of alcohol310 (123 mg, 0.286 mmol) in 5 mL of CH₂Cl₂. After 72 h the mixture wasfiltered through a 45, Nylon syringe filter, concentrated in vacuo, andpurified via flash column chromatography (5-60% EtOAc/hexanes gradient)to afford ketone 311. LRMS (APCI) calc'd for (C₂₇H₃₀NO₂Si) [M+H]+,428.2; found 428.2.

Example 42

7-(hydroxymethyl)-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one

Tetra-n-butylammonium fluoride (8 μL of a 2M solution in THF, 0.15 mmol)was added to a solution of ketone 311 (58 mg, 0.14 mmol) in 1 mL of THF.After 30 min, the solution was poured into EtOAc, washed with water andbrine then dried over Na₂SO₄. The solution was filtered, concentrated invacuo and purified via flash column chromatography (10-100%EtOAc/hexanes gradient) to afford alcohol 312. ¹H NMR (600 MHz, CDCl₃) δ9.08 (d, 1H); 8.68 (d, 1H); 8.21 (s, 1H); 7.68 (dd, 1H); 7.64-7.67 (m,2H); 7.57 (s, 1H); 7.44-7.48 (m, 2H); 7.37-7.41 (m, 1H); 7.35 (d, 1H);7.23 (d, 1H); 4.81 (s, 2H).

Example 43

7-({[tert-butyl(dimethyl)silyl]oxy}methyl)-3-chloro-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one

Compound 313 was prepared in a manner analogous to that described inExample 41 with the exception that diisobutylaluminum hydride was usedas the reducing agent. LRMS (APCI) calc'd for (C₂₁H₂₅ClNO₂Si) [M+H]+,386.1; found 385.7.

Example 44

7-({[tert-butyl(dimethyl)silyl]oxy}methyl)-3-(1-methyl-1H-pyrazol-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one

Compound 313 (185 mg, 0.479 mmol),1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(199 mg, 0.959 mmol), Pd(dppf)Cl₂ (35 mg, 0.048 mmol) and K₂CO₃ (199 mg,1.44 mmol) were suspended in 3 mL of dioxane. The mixture was spargedwith Ar for 10 min, then heated to 95° C. After 18 h, the mixture waspoured into EtOAc, washed with saturated aqueous NaHCO₃ and brine thendried over Na₂SO₄. The solution was filtered, concentrated in vacuo, andpurified via flash column chromatography (10-100% EtOAc/hexanesgradient) to afford title compound 314. LRMS (APCI) calc'd for(C₂₅H₃₀N₃O₂Si) [M+H]+, 432.2; found 431.7.

Example 45

7-(hydroxymethyl)-3-(1-methyl-1H-pyrazol-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one

Compound 315 was prepared from Compound 228 in a manner analogous tothat described in Example 42. ¹H NMR (600 MHz, CDCl₃) δ 9.02 (d, 1H);8.57 (d, 1H); 8.26 (d, 1H); 7.92 (d, 1H); 7.81 (s, 1H); 7.73 (dd, 1H);7.62 (dd, 1H); 7.36 (d, 1H); 7.25 (d, 1H); 4.86 (d, 2H); 3.99 (s, 3H);1.84 (t, 1H). LRMS (APCI) calc'd for (C₁₉H₁₆N₃O₂) [M+H]+, 318.1; found317.8.

Example 46

[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methylacetate (Compound 316)

Compound 315 (12 mg, 0.038 mmol) was dissolved in 0.5 mL dichloromethaneand 0.1 mL N,N′-dimethylformamide and cooled to 0° C. DMAP (2 mg, 0.019mmol) and triethylamine (20 μL, 0.14 mmol) were added followed by acetylchloride (7 μL, 0.10 mmol). The mixture was stirred at 0° C. for 3 h atwhich time it was quenched with saturated aqueous ammonium chloride andextracted three times with dichloromethane. The combined organics weredried over magnesium sulfate, filtered, concentrated in vacuo.Purification via reverse phase HPLC (10-100% acetonitrile/watergradient, 0.05% trifluoroacetic acid modifier) afforded the titlecompound. ¹H NMR (600 MHz, CDCl₃) δ 9.02 (s, 1H); 8.59 (s, 1H); 8.26 (s,1H); 7.93 (s, 1H); 7.83 (s, 1H); 7.68 (d, 1H); 7.61 (d, 1H); 7.40 (d,1H); 7.26-7.24 (m, 1H); 5.24 (s, 2H); 3.99 (s, 3H); 2.14 (s, 3H). LRMS(APCI) calc'd for (C₂₁H₁₈N₃O₃) [M+H]+, 360.1; found 360.1.

Example 47

[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methylbenzoate (Compound 317)

Compound 315 (10 mg, 0.032 mmol) was dissolved in 0.5 mL dichloromethaneand 0.1 mL N,N′-dimethylformamide and cooled to 0° C. DMAP (2 mg, 0.019mmol) and triethylamine (16 μL, 0.12 mmol) were added followed bybenzoyl chloride (10 μL, 0.08 mmol). The mixture was stirred at 0° C.for 3 h at which time it was quenched with saturated aqueous ammoniumchloride and extracted three times with dichloromethane. The combinedorganics were dried over magnesium sulfate, filtered, concentrated invacuo. Purification via reverse phase HPLC (10-100% acetonitrile/watergradient, 0.05% trifluoroacetic acid modifier) afforded the titlecompound. ¹H NMR (600 MHz, CDCl₃) δ 9.03 (s, 1H); 8.62 (s, 1H); 8.36 (s,1H); 8.09 (d, 2H); 7.93 (s, 1H); 7.83 (s, 1H); 11.73 (d, 1H); 7.64 (d,1H); 7.58 (t, 1H); 7.45 (t, 2H); 7.42-7.41 (m, 1H); 7.27 (d, 1H); 5.50(s, 2H); 3.99 (s, 3H). LRMS (APCI) calc'd for (C₂₆H₂₀N₃O₃) [M+H]+,422.1; found 422.1.

Example 48

Step 1:

Methanesulfonyl chloride (1 drop from a 22G needle) was added to asolution of Compound 312 (30.0 mg, 0.096 mmol) and NEt₃ (27 μL, 0.19mmol) at 0° C. After 30 min, additional methanesulfonyl chloride (1 dropfrom a 22G needle) was added. After 30 min, additional methanesulfonylchloride (2 drops from a 22G needle) was added. After an additional 2 h,the reaction mixture was poured into EtOAc, washed with saturatedaqueous NaHCO₃ and brine then dried over Na₂SO₄. The solution wasfiltered, concentrated in vacuo and the crude mesylate was used directlyin the next reaction.

Step 2:

The crude mesylate from Step A (37 mg, 0.01 mmol) and sodiummethanesulfinate (19 mg, 0.19 mmol) were suspended in 2 mL of DMF andheated to 45° C. After 1 h, the reaction mixture was poured into EtOAc,washed with water and brine then dried over Na₂SO₄. The solution wasfiltered and concentrated in vacuo to give a mixture of Compounds 318and 319. The two compounds were purified by reverse phase HPLC (30-100%CH₃CN/water with a 0.1% TFA modifier) to provide the TFA salts.7-[(methylsulfonyl)methyl]-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one(Compound 318). ¹H NMR (600 MHz, CDCl₃) δ 9.27 (d, 1H); 8.88 (d, 1H);8.29 (s, 1H); 7.83 (dd, 1H); 7.68-7.73 (m, 3H); 7.46-7.55 (m, 4H); 7.37(d, 1H); 4.41 (s, 2H); 2.85 (s, 3H). LRMS (APCI) calc'd for (C₂₂H₁₈NO₃S)[M+H]+, 376.1; found 376.1.

(5-oxo-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)methylmethanesulfinate (Compound 319). ¹H NMR (600 MHz, CDCl₃) δ 9.29 (d, 1H);8.98 (d, 1H); 8.25 (d, 1H); 7.73 (dd, 1H); 7.67-7.70 (m, 2H); 7.64 (d,1H); 7.39-7.52 (m, 5H); 5.15 (ABq, 2H); 2.68 (s, 3H). LRMS (APCI) calc'dfor (C₂₂H₁₈NO₃S) [M+H]+, 376.1; found 376.1.

Example 49

7-(aminomethyl)-3-(1-methyl-1H-pyrazol-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one

Diphenyl phosphoryl azide (DPPA) (1 drop from a 21G needle) and1,8-dizabicyclo[5.4.0]undec-7-ene (DBU) (1 drop from a 21G needle) wereadded to a solution of Compound 315 (10.0 mg, 0.032 mmol) in 1 mL ofTHF. After 18 h, additional DPPA (2 drops from a 21G needle) and DBU (2drops from a 21G needle) were added. After a further 24 h, additionalDPPA (4 drops from a 21G needle) and DBU (4 drops from a 21G needle)were added. After another 24 h, the solution was diluted in EtOAc,washed with saturated aqueous NaHCO₃ and brine then dried over Na₂SO₄.The solution was filtered, concentrated in vacuo and the crude azide wasused directly in the next reaction.

The crude azide was dissolved in 5 mL of MeOH and SnCl₂ (18.2 mg, 0.10mmol) was added. After 30 min, additional SnCl₂ (36.4 mg, 0.20 mmol) wasadded. After a further 18 h, additional SnCl₂ (18.2 mg, 0.10 mmol) wasadded. After 3 h, the solution was concentrated in vacuo and purified byreverse phase HPLC (20-100% CH₃CN/water with a 0.05% TFA modifier).toafford the title compound 320. ¹H NMR (600 MHz, CD₃OD) δ 9.05 (d, 1H);8.60 (d, 1H); 8.20-8.23 (m, 2H); 8.01 (s, 1H); 7.75 (dd, 1H); 7.70 (d,1H); 7.34 (d, 1H); 7.27 (d, 1H); 4.03 (s, 2H); 3.95 (s, 3H). LRMS (APCI)calc'd for (C₁₉H₁₇N₄O) [M+H]+, 317.1; found 317.1.

Example 50

N-{[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methyl}methanesulfonamide

Compound 315 was converted to the corresponding mesylate in a manneranalogous to that described in Example 48 Step 1. The crude mesylate wasdissolved in 5 mL of THF and methanesulfonamide (60 mg, 0.63 mol) andK₂CO₃ (87 mg, 0.63 mmol) were added. After 30 min, the mixture washeated to 55° C., then 1 mL of DMF was added. After another 1 h, anadditional 1 mL of DMF was added. After 18 h, the mixture was diluted inEtOAc, washed with saturated aqueous NaHCO₃ and brine then dried overNa₂SO₄. The solution was filtered, concentrated in vacuo and purified byreverse phase HPLC (30-100% CH₃CN/water with a 0.05% TFA modifier).toafford the title compound 321. ¹H NMR (600 MHz, CDCl₃) δ 9.02 (d, 1H);8.58 (s, 1H); 8.23 (s, 1H); 7.92 (s, 1H); 7.83 (s, 1H); 7.72 (dd, 1H);7.61 (d, 1H); 7.39 (d, 1H); 7.22 (d, 1H); 4.89 (br s, 1H); 4.47-4.49 (m,2H); 3.99 (s, 3H); 2.97 (s, 3H). LRMS (APCI) calc'd for (C₂₀H₁₉N₄O₃S)[M+H]+, 395.1; found 395.1.

Example 51

N-(5-oxo-3-phenyl-10,11-dihydro-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)methanesulfonamide

Compound 263 (15 mg, 0.04 mmol) was dissolved in 8 mL of EtOH and 1 mLof 1 N HCl, then 4 mg of 10% palladium on carbon was added and themixture was placed under 45 psi of hydrogen on a Parr shaker. After 24 hthe reaction mixture was filtered through a 45μ Nylon syringe filter,concentrated in vacuo, and purified by reverse phase HPLC (10-60%CH₃CN/water with a 0.1% TFA modifier) to afford the over-reducedbenzylic alcohol:N-(5-hydroxy-3-phenyl-10,11-dihydro-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)methanesulfonamide.

The crude benzylic alcohol (5 mg, 0.013 mmol) was dissolved in 5 mL ofCH₂Cl₂ and stirred with 25 mg of MnO₂ for 2 h. The reaction mixture wasfiltered through a 45, Nylon syringe filter, concentrated in vacuo, andpurified by reverse phase HPLC (30-100% CH₃CN/water with a 0.1% TFAmodifier).to afford the title compound 322. ¹H NMR (600 MHz, CDCl₃) δ8.83 (d, 1H); 8.54 (d, 1H); 7.65 (d, 1H); 7.57-7.59 (m, 2H); 7.41-7.47(m, 3H); 7.35-7.39 (m, 1H); 7.25 (d, 1H); 6.57 (s, 1H); 3.43-3.46 (m,2H); 3.18-3.22 (m, 2H); 2.98 (s, 3H). LRMS (APCI) calc'd for(C₂₁H₁₉N₂O₃S) [M+H]+, 379.1; found 379.1.

Example 52

7-amino-6-chloro-3-(1-methyl-1H-pyrazol-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one

N-chlorosuccinimide (5 mg, 0.036 mmol) was added to a solution ofCompound 139 (10 mg, 0.033 mmol) in dry acetonitrile and heated to 75°C. After three hours, 1 molar sodium hydroxide was added and the mixturewas extracted with dichloromethane, dried over magnesium sulfate,filtered, concentrated in vacuo, and purified by reverse phase HPLC(10-70% acetonitrile/water gradient 0.1%, trifluoroacetic acid modifier)to afford the title compound. ¹H NMR (600 MHz, CDCl₃) δ8.99 (d, 1H);8.25 (d, 1H); 8.23 (d, 1H); 8.03 (s, 1H); 7.36 (d, 1H); 7.19 (d, 1H);7.08 (d, 1H); 7.01 (d, 1H); 3.96 (s, 3H). LRMS (APCI) calc'd for(C₁₈H₁₄ClN₄O) [M+H]+, 337.1; found 337.1.

Example 53

methyl7-{[(dimethylamino)sulfonyl]amino}-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-3-carboxylate(Compound 324)

Compound 45 (100 mg, 0.275 mmol), 1,8-diazabicyclo{5.4.0}undec-7-ene(0.113 mL, 0.825 mmol), tri-t-butylphosphonium tetrafluoroborate (0.032g, 0.032 mmol), palladium(I)acetate (6 mg, 0.027 mmol), andmolybdenumhexacarbonyl (73 mg, 0.275 mmol) were dissolved in 2 mL of DMFand 1 mL of methanol. The reaction mixture was heated in the BiotageInitiator series microwave at 130° C. for 30 minutes. The mixture wasdiluted in ethylacetate and the organic layer was washed with saturatedaqueous sodium bicarbonate and brine, then dried over sodium sulfate andconcentrated. The residue was purified via reverse phase HPLC (30-100%acetonitrile/water gradient, 0.05% trifluoroacetic acid modifier) toafford the title compound. ¹H NMR (600 MHz, DMSO-d₆) δ 10.59 (s, 1H);9.32 (d, 1H); 8.89 (d, 1H); 8.01 (d, 1H); 7.80 (d, 1H); 7.61 (dd, 1H);7.51 (d, 1H); 7.29 (d, 1H); 3.92 (s, 3H); 2.73 (s, 6H). LRMS (APCI)calc'd for (C₁₈H₁₇N₃O₅S) [M+H]+, 388.1; found 388.1.

Example 54

7-{[(dimethylamino)sulfonyl]amino}-5-oxo-N-1,3-thiazol-2-yl-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-3-carboxamide(Compound 325)

methyl7-{[(dimethylamino)sulfonyl]amino}-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-3-carboxylate(17 mg, 0.044 mmol) was dissolved in 1 mL of THF and 1 mL of 1 M aqueoussodium hydroxide. After 2 h the mixture was quenched by the addition of1.1 mL of 1M HCl and the organics were removed in vacuo. The materialwas freeze dried to afford7-{[(dimethylamino)sulfonyl]amino}-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-3-carboxylicacid.

The crude7-{[(dimethylamino)sulfonyl]amino}-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-3-carboxylicacid (21 mg, 0.056 mmol), 2-aminothiazole (8 mg, 0.084 mmol),N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (16 mg,0.084 mmol), 1-hydroxybenzotriazole hydrate (11 mg, 0.084 mmol) and4-dimethylaminopyridine (spatula tip) were dissolved in 2 mL of DMF andstirred for 18 h. The mixture was diluted in ethylacetate and theorganic layer was washed with saturated aqueous sodium bicarbonate andbrine, then dried over sodium sulfate and concentrated. The residue waspurified via reverse phase HPLC (20-100% acetonitrile/water gradient,0.05% trifluoroacetic acid modifier) to afford the title compound. ¹HNMR (600 MHz, DMSO-d6) δ 13.06 (br s, 1H); 10.59 (br s, 1H); 9.47 (d,1H); 9.13 (d, 1H); 8.02 (d, 1H); 7.81 (d, 1H); 7.61 (dd, 1H); 7.57 (d,1H); 7.50 (d, 1H); 7.27-7.33 (m, 2H); 2.74 (s, 6H); LRMS (APCI) calc'dfor (C₂₀H₁₇N₅O₄S₂) [M+H]+, 456.1; found 456.1.

Example 55

3-chloro-7-vinyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one (Compound326)

A test tube fitted with a teflon septum was charged with compound 1 (1.0g, 3.1 mmol), PdCl₂(dppf) (0.12 g, 0.16 mmol), and potassiumvinyltrifluoroborate (0.42 g, 3.1 mmol). The tube was evacuated andbackfilled with argon three times. Fully degassed n-PrOH (30 mL) wasadded followed by the addition of triethylamine (1.3 mL, 9.4 mmol). Themixture was heated to 100° C. for 3 hours. The solution was diluted withethyl acetate and washed with water and brine and dried over magnesiumsulfate. The solution was concentrated in vacuo and purified via flashchromatography (silica, 0-25% ethyl acetate/hexanes) to afford the titlecompound. ¹H NMR (600 MHz, CDCl₃) δ 8.80 (d, 1H); 8.53 (d, 1H); 8.27 (d,1H); 7.76 (dd, 1H); 7.57 (d, 1H); 7.32 (d, 1H); 7.26 (d, 1H); 6.83 (dd,1H); 5.94 (d, 1H); 5.43 (d, 1H). LRMS (APCI) calc'd for (C₁₆H₁₁ClNO)[M+H]+, 268.1; found 268.1.

Example 56

3-chloro-7-oxiran-2-yl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one(Compound 327)

3-chloro-7-vinyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one (0.30 g,1.12 mmol) was dissolved in 17 mL DMSO and 3.0 mL water.N-Bromosuccinimide (0.20 g, 1.12 mmol) was added and the reaction washeated in an oil bath at 60° C. for 1 hour at which time an additional0.1 g N-Bromosuccinimide (0.56 mmol) was added and the mixture wasstirred an additional 45 min at 60° C. The resulting mixture was dilutedwith water and extracted with ethyl acetate three times. The combinedorganics were washed with brine, dried over sodium sulfate, filtered,and concentrated in vacuo. The resulting crude residue was dissolved in30 mL tetrahydrofuran and 6 mL t-BuOH. t-BuOK (2.24 mL of 1.0 M in THF,2.24 mmol) was added dropwise and the resulting orange slurry wasstirred at room temperature for 45 min. The reaction was diluted withwater and extracted with ethyl acetate three times. The combinedorganics were washed with brine, dried over magnesium sulfate,concentrated in vacuo, and purified via flash chromatography (silica,0-25% ethyl acetate/hexanes) to afford the title compound. ¹H NMR (600MHz, CDCl₃) δ 8.79 (d, 1H); 8.49 (d, 1H); 8.20 (d, 1H); 7.57 (d, 1H);7.55 (dd, 1H); 7.27 (d, 1H); 7.23 (d, 1H); 3.99 (dd, 1H); 3.21 (dd, 1H);2.84 (dd, 1H).

Example 57

3-chloro-7-oxiran-2-yl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one (0.67g, 2.4 mmol) was dissolved in 30 mL THF. LiAlH₄ (90 mg, 2.4 mmol) wasadded and the reaction was stirred at room temperature for 2 hours. Thereaction was quenched via the dropwise addition of water followed byslow addition of 1N HCl. The mixture was extracted with ethyl acetate.The combined organics were washed with brine, dried over magnesiumsulfate, filtered, and concentrated in vacuo. The crude mixture was usedwithout further purification.

3-chloro-7-(1-hydroxyethyl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-ol

LRMS (APCI) calc'd for (C₁₆H₁₅ClNO₂) [M+H]+, 288.1; found 288.1.

3-chloro-7-(2-hydroxyethyl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-ol

LRMS (APCI) calc'd for (C₁₆H₁₅ClNO₂) [M+H]+, 288.1; found 288.1.

Example 58

A crude mixture of3-chloro-7-(1-hydroxyethyl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-oland3-chloro-7-(2-hydroxyethyl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-ol(0.67 g, 2.4 mmol) was dissolved in 30 mL N.N′-dimethylformamide.Imidazole (0.82 g, 6.0 mmol) and TBSCl (0.45 g, 3.0 mmol) were addedsequentially and the reaction was stirred at 50° C. for 2 hours at whichtime additional imidazole (0.82 g, 12 mmol) and TBSCl (0.45 g, 3.0 mmol)were added and the reaction was stirred an additional 2 hours. Themixture was diluted with water and saturated aqueous ammonium chlorideand extracted three times with ethyl acetate. The combined organics werewashed five times with brine, dried over magnesium sulfate andconcentrated in vacuo. The resulting crude material was dissolved in 30mL dichloromethane. MnO₂ (4.0 g, 46.5 mmol) was added and the reactionwas stirred overnight at room temperature. The resulting slurry wasfiltered through a plug of celite with dichloromethane, concentrated invacuo, and purified via flash chromatography (silica, 0-20% ethylacetate/hexanes) to afford the title compounds as a mixture. Thecompounds were separated via flash chromatography (silica, 0-10% ethylacetate/hexanes).

7-(1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-3-chloro-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one.¹H NMR (600 MHz, CDCl₃) δ 8.79 (d, 1H); 8.53 (d, 1H); 8.18 (d, 1H); 7.76(dd, 1H); 7.58 (d, 1H); 7.29 (d, 1H); 7.26 (d, 1H); 5.01 (q, 1H); 1.44(d, 3H); 0.91 (s, 9H); 0.07 (s, 3H); −0.01 (s, 3H).

7-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-3-chloro-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one.¹H NMR (600 MHz, CDCl₃) δ 8.80 (d, 1H); 8.52 (d, 1H); 8.12 (d, 1H); 7.58(dd, 1H); 7.53 (d, 1H); 7.29-7.27 (m, 2H); 3.86 (t, 2H); 2.96 (t, 2H);0.84 (s, 9H); −0.04 (s, 6H).

Example 59

7-(1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-3-(1-methyl-1H-pyrazol-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one(Compound 332)

A test tube fitted with a teflon septum was charged with7-(1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-3-chloro-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one(50 mg, 0.13 mmol), PdCl₂(PPh₃)₂ (9 mg, 0.013 mmol),1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (78mg, 0.38 mmol), and sodium carbonate (40 mg, 0.38 mmol). The tube wasevacuated and backfilled with argon three times. Fully degassed dioxane(1,2 mL) was added and the mixture was stirred at 100° C. overnight. Thesolution was diluted with ethyl acetate, washed with water and brine,dried over magnesium sulfate, concentrated in vacuo, and purified viaflash chromatography (silica, 20-100% ethyl acetate/hexanes) to affordthe title compound. ¹H NMR (600 MHz, CDCl₃) δ 8.99 (d, 1H); 8.58 (d,1H); 8.19 (d, 1H); 7.90 (d, 1H); 7.97 (s, 1H); 7.72 (dd, 1H); 7.56 (d,1H); 7.32 (d, 1H); 7.22 (d, 1H); 5.01 (q, 1H); 3.97 (s, 3H); 1.44 (d,3H); 0.90 (s, 9H); 0.06 (s, 3H); −0.02 (s, 3H). LRMS (APCI) calc'd for(C₂₆H₃₂N₃O₂Si) [M+H]+, 446.2; found, 446.2.

Example 60

7-(1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-3-(1-methyl-1H-pyrazol-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one(51 mg, 0.114 mmol) was dissolved in 2 mL of tetrahydrofuran.Tetrabutylammonium fluoride (0.14 mL of 1.0M in THF, 0.14 mmol) wasadded and the mixture was stirred at room temperature for 1 hour. Thereaction was diluted with ethyl acetate and brine and washed with brinetwice. The organic layer was dried over magnesium sulfate, filtered andconcentrated in vacuo. Purification via reverse phase HPLC (10-70%acetonitrile/water gradient, 0.05% trifluoroacetic acid modifier)afforded the title compound. The two enantiomers were separated viapreparative chiral HPLC (AS column, 18% ethanol/heptane isocratic).Absolute stereochemistry was determined via formation of the Mosher'sesters.

7-[(1R)-1-hydroxyethyl]-3-(1-methyl-1H-pyrazol-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one.¹H NMR (600 MHz, CDCl₃) δ 8.98 (d, 1H); 8.55 (d, 1H); 8.24 (d, 1H); 7.89(d, 1H); 7.80 (s, 1H); 7.74 (dd, 1H); 7.58 (d, 1H); 7.34 (d, 1H); 7.22(d, 1H); 5.06 (q, 1H); 3.98 (s, 3H); 1.55 (s, 3H). Hydroxyl proton wasnot observed. LRMS (APCI) calc'd for (C₂₀H₁₈N₃O₂) [M+H]+, 332.1; found332.1. τ_(R): 18.9 min (analytical chiral HPLC, AS column, 0.46 cm×25cm, 18% ethanol/heptane, isocratic, flow rate=0.75 mL/min).

7-[(1S)-1-hydroxyethyl]-3-(1-methyl-1H-pyrazol-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one.¹H NMR and LRMS data matched7-[(1R)-1-hydroxyethyl]-3-(1-methyl-1H-pyrazol-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one.τ_(R): 21.5 min (analytical chiral HPLC, AS column, 0.46 cm×25 cm, 18%ethanol/heptane, isochratic, flow rate=0.75 mL/min).

Example 61

7-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-3-(1-methyl-1H-pyrazol-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one(Compound 335)

A test tube fitted with a teflon septum was charged with7-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-3-chloro-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one(9 mg, 0.023 mmol), PdCl₂(PPh₃)₂ (2 mg, 0.002 mmol),1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (14mg, 0.068 mmol), and sodium carbonate (7 mg, 0.068 mmol). The tube wasevacuated and backfilled with argon three times. Fully degassed dioxane(0.5 mL) was added and the mixture was stirred at 100° C. overnight. Thesolution was diluted with ethyl acetate, washed with water and brine,dried over magnesium sulfate, concentrated in vacuo, and purified viaflash chromatography (silica, 20-100% ethyl acetate/hexanes) to affordthe title compound. LRMS (APCI) calc'd for (C₂₆H₃₂N₃O₂Si) [M+H]+, 446.2;found 446.2.

Example 62

7-(2-hydroxyethyl)-3-(1-methyl-1H-pyrazol-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one(Compound 336)

7-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-3-(1-methyl-1H-pyrazol-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one(5 mg, 0.011 mmol) was dissolved in 0.5 mL of tetrahydrofuran.Tetrabutylammonium fluoride (0.013 mL of 1.0M in THF, 0.013 mmol) wasadded and the mixture was stirred at room temperature for 1 hour. Thereaction was diluted with ethyl acetate and brine and washed with brinetwice. The organic layer was dried over magnesium sulfate, filtered andconcentrated in vacuo. Purification via reverse phase HPLC (10-70%acetonitrile/water gradient, 0.05% trifluoroacetic acid modifier)afforded the title compound. ¹H NMR (600 MHz, CDCl₃) δ 9.01 (d, 1H);8.58 (s, 1H); 8.16 (d, 1H); 7.92 (s, 1H); 7.81 (s, 1H); 7.59 (dd, 1H);7.56 (d, 1H); 7.35 (d, 1H); 7.24 (d, 1H); 3.99 (s, 3H); 3.96 (t, 2H);3.03 (t, 2H). Hydroxyl proton was not observed. LRMS (APCI) calc'd for(C₂₀H₁₈N₃O₂) [M+H]+, 332.1; found 332.1.

Example 63

3-chloro-7-(1-hydroxyethyl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one(Compound 337)

7-(1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-3-chloro-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one(20 mg, 0.05 mmol) was taken up in 1 mL of tetrahydrofuran.Tetrabutylammonium fluoride (0.06 mL of 1.0M in THF, 0.06 mmol) wasadded and the mixture was stirred at room temperature for 45 min. Thereaction was concentrated in vacuo and directly purified via flashchromatography (silica, 0-35% ethyl acetate/hexanes) to afford the titlecompound. ¹H NMR (600 MHz, CDCl₃) δ 8.80 (d, 1H); 8.50 (d, 1H); 8.23 (d,1H); 7.76 (dd, 1H); 7.60 (d, 1H); 7.31 (d, 1H); 7.26 (d, 1H); 5.06 (q,1H); 1.55 (d, 3H). Hydroxyl proton was not observed. LRMS (APCI) calc'dfor (C₁₆H₁₃ClNO₂) [M+H]+, 286.1; found 286.1.

Example 64

3-chloro-7-ethyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-ol (Compound338)

3-chloro-7-vinyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one (20 mg,0.075 mmol) was dissolved in 1 mL of tetrahydrofuran. Rh(COD)₂BF₄ (3 mg,0.007 mmol) was added followed by a dropwise addition of 9-BBN (0.44 mLof 0.5 M in THF, 0.22 mmol) and the reaction was stirred overnight. Thereaction was cooled to 0° C. and quenched by the simultaneous additionof 1M sodium hydroxide (2.5 ml) and 30% aqueous hydrogen peroxide (0.75mL) and stirred for 5 hours. The resulting solution was poured intoethyl acetate and brine and extracted three times with ethyl acetate.The combined organics were dried over magnesium sulfate, dried overmagnesium sulfate, concentrated in vacuo, and purified via flashchromatography (0-60% ethyl acetate/hexanes) to afford the titlecompound. ¹H NMR (600 MHz, CDCl₃) δ 8.41 (s, 1H); 8.03 (s, 1H); 7.54 (s,1H); 7.28 (m, 2H); 7.17-7.14 (m, 2H); 5.31 (s, 1H); 2.70 (q, 2H); 1.25(t, 3H). Hydroxyl proton was not observed. LRMS (APCI) calc'd for(C₁₆H₁₅ClNO) [M+H]+, 272.1; found 272.1.

Example 65

3-chloro-7-(1,2-dihydroxyethyl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one(Compound 339)

3-chloro-7-vinyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one (0.10 g,0.37 mmol) was dissolved in 4 mL of tetrahydrofuran and 2 mL water.4-Methylmorpholine N-oxide (0.105 mL of a 50% w/w aqueous solution, 0.45mmol) was added followed by osmium tetroxide (0.24 mL of a 4% w/waqueous solution, 0.037 mmol). The resulting mixture was stirred at roomtemperature for 3 hours at which time it was quenched via the additionof a 10% w/w aqueous sodium thiosulfate solution and stirred for 10minutes. The mixture was extracted with ethyl acetate two times. Thecombined organics were dried over magnesium sulfate, filtered,concentrated in vacuo, and purified via flash chromatography (silica,20-100% ethyl acetate/hexanes) to afford the title compound. ¹H NMR (600MHz, CDCl₃) δ 8.80 (d, 1H); 8.49 (d, 1H); 8.24 (d, 1H); 7.76 (dd, 1H);7.60 (d, 1H); 7.32 (d, 1H); 7.25 (d, 1H); 4.99 (dd, 1H); 3.87 (dd, 1H);3.70 (dd, 1H). Hydroxyl protons were not observed. LRMS (APCI) calc'dfor (C₁₆H₁₃ClNO₃) [M+H]+, 302.1; found 302.1.

Example 66

7-(1,2-dihydroxyethyl)-3-(1-methyl-1H-pyrazol-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one(Compound 340)

A test tube fitted with a teflon septum was charged with3-chloro-7-(1,2-dihydroxyethyl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one(9 mg, 0.03 mmol),1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (12mg, 0.060 mmol), Pd₂(dba)₃ (1 mg, 0.001 mmol), (tBu₃)PBF₄ (1 mg, 0.003mmol) and potassium fluoride (6 mg, 0.098 mmol). The tube was evacuatedand backfilled with argon three times. Fully degassed DMF (0.9 mL) wasadded and the reaction was heated in a microwave at 180° C. for 30 min.The reaction was poured into an ethyl acetate/brine mixture and washedtwice with brine. The organic layer was dried over magnesium sulfate,filtered, concentrated in vacuo, and purified via reverse phase HPLC(10-70% acetonitrile/water gradient, 0.05% trifluoroacetic acidmodifier) to afford the title compound. ¹H NMR (600 MHz, CDCl₃) δ 9.00(d, 1H); 8.58 (d, 1H); 8.27 (s, 1H); 7.91 (s, 1H); 7.81 (s, 1H); 7.75(d, 1H); 7.61 (d, 1H); 7.38 (d, 1H); 7.24 (d, 1H); 5.0 (dd, 1H); 3.99(s, 3H); 3.87 (dd, 1H); 3.72 (d, 1H). Hydroxyl protons were notobserved. LRMS (APCI) calc'd for (C₂₀H₁₈N₃O₃) [M+H]+, 348.1; found348.1.

Example 67

3-chloro-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-7-carbaldehyde(Compound 341)

3-chloro-7-(1,2-dihydroxyethyl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one(60 mg, 0.20 mmol) was dissolved in 1.8 mL of tetrahydrofuran and 0.9 mLwater. Sodium periodate (51 mg, 0.24 mmol) was added and the reactionwas stirred at room temperature for 1 hour. The reaction was thendiluted with water and extracted with ethyl acetate three times. Thecombined organics were dried over magnesium sulfate, filtered,concentrated in vacuo, and purified via flash chromatography (silica,10-100% ethyl acetate/hexanes) to afford the title compound. ¹H NMR (600MHz, CDCl₃) δ 10.15 (s, 1H); 8.85 (d, 1H); 8.73 (d, 1H); 8.54 (d, 1H);8.20 (dd, 1H); 7.75 (d, 1H); 7.47 (d, 1H); 7.31 (d, 1H).

Example 68

3-chloro-7-(1-hydroxypropyl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one(Compound 342)

3-chloro-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-7-carbaldehyde (25mg, 0.093 mmol) was dissolved in 4 mL of hot dichloromethane. Thesolution was cooled to room temperature and ethylmagnesium chloride(0.047 mL of 2.0 M in THF, 0.093 mmol) was added. The reaction wasstirred at room temperature for 1.5 hours at which point it was quenchedvia the addition of saturated aqueous ammonium chloride. The mixture wasextracted three times with dichloromethane. The combined organic layerswere dried over magnesium sulfate, filtered, concentrated in vacuo, andpurified via flash chromatography (silica, 5-60% ethyl acetate/hexanes)to afford the title compound. ¹H NMR (600 MHz, CDCl₃) δ 8.80 (d, 1H);8.52 (d, 1H); 8.21 (d, 1H); 7.73 (dd, 1H); 7.60 (d, 1H); 7.32 (d, 1H);7.27 (d, 1H); 4.79 (t, 1H); 1.99 (s, 1H); 1.89-1.79 (m, 2H); 0.94 (t,3H). LRMS (APCI) calc'd for (C₁₇H₁₅ClNO₂) [M+H]+, 300.1; found 300.1.

Example 69

7-[(1R)-1-methoxyethyl]-3-(1-methyl-1H-pyrazol-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one(Compound 343)

7-[(1R)-1-hydroxyethyl]-3-(1-methyl-1H-pyrazol-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one(7 mg, 0.02 mmol) was dissolved in 1 mL of tetrahydrofuran. Sodiumhydride (10 mg of 60% dispersion in oil) was added and the reaction wasstirred at room temperature for 2 hours. Methyl iodide (26 μL, 0.42mmol) was added and the reaction was stirred an additional 3 hours. Thereaction was then poured into a mixture of ethyl acetate and saturatedaqueous ammonium chloride. The aqueous layer was extracted twice withethyl acetate. The combined organics were dried over magnesium sulfate,filtered, concentrated in vacuo, and purified via reverse phase HPLC(10-100% acetonitrile/water gradient, 0.05% trifluoroacetic acidmodifier) to afford the title compound. ¹H NMR (600 MHz, CDCl₃) δ 9.05(d, 1H); 8.73 (s, 1H); 8.21 (d, 1H); 7.94 (s, 1H); 7.85 (s, 1H); 7.73(dd, 1H); 7.65 (d, 1H); 7.51 (d, 1H); 7.34 (d, 1H); 4.47 (q, 1H); 4.01(s, 3H); 3.27 (s, 3H); 1.46 (d, 3H). LRMS (APCI) calc'd for (C₂₁H₂₀N₃O₂)[M+H]+, 346.2; found 346.2.

Example 70

7-[(1S)-1-methoxyethyl]-3-(1-methyl-1H-pyrazol-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one(Compound 344)

7-[(1S)-1-hydroxyethyl]-3-(1-methyl-1H-pyrazol-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one(7 mg, 0.02 mmol) was dissolved in 1 mL of tetrahydrofuran. Sodiumhydride (10 mg of 60% dispersion in oil) was added and the reaction wasstirred at room temperature for 2 hours. Methyl iodide (26 μL, 0.42mmol) was added and the reaction was stirred an additional 3 hours. Thereaction was then poured into a mixture of ethyl acetate and saturatedaqueous ammonium chloride. The aqueous layer was extracted twice withethyl acetate. The combined organics were dried over magnesium sulfate,filtered, concentrated in vacuo, and purified via reverse phase HPLC(10-100% acetonitrile/water gradient, 0.05% trifluoroacetic acidmodifier) to afford the title compound. ¹H NMR and LRMS data matched7-[(1R)-1-methoxyethyl]-3-(1-methyl-1H-pyrazol-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one.

Example 71

tert-butyl4-[2-(3-chloro-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)-2-hydroxyethyl]piperazine-1-carboxylate(Compound 345)

3-chloro-7-oxiran-2-yl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one (60mg, 0.21 mmol) was suspended in 2.5 mL of methanol. tert-Butylpiperazine-1-carboxylate (98 mg, 0.53 mmol) was added and the reactionwas heated to reflux for 8 hours. The resulting mixture was concentratedin vacuo and purified directly via flash chromatography (15-100% ethylacetate/hexanes) to afford the title compound. ¹H NMR (600 MHz, CDCl₃) δ9.79 (d, 1H); 8.49 (d, 1H); 8.22 (d, 1H); 7.77 (dd, 1H); 7.60 (d, 1H);7.31 (d, 1H); 7.25 (d, 1H); 4.91 (dd, 1H); 3.50-3.45 (m, 4H); 2.72(broad s, 2H); 2.63 (dd, 1H); 2.50 (dd, 1H); 2.44 (broad s, 2H); 1.46(s, 9H). Hydroxyl proton was not observed. LRMS (APCI) calc'd for(C₂₅H₂₉ClN₃O₄) [M+H]+, 470.2; found 470.2.

Example 72

tert-butyl4-{2-hydroxy-2-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]ethyl}piperazine-1-carboxylate(Compound 346)

tert-Butyl4-[2-(3-chloro-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)-2-hydroxyethyl]piperazine-1-carboxylate(65 mg, 0.138 mmol),1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (58mg, 0.28 mol), Pd₂(dba)₃ (6 mg, 0.007 mmol), (tBu₃)PBF₄ (4 mg, 0.014mmol), and potassium fluoride (27 mg, 0.46 mmol) were combined in asealed tube which was evacuated and backfilled with argon three times.Fully degassed DMF (1.5 mL) was added. The tube was placed in an oilbath at 115° C. and stirred for 19 hours. The reaction mixture waspoured into an ethyl acetate/brine mixture and extracted with ethylacetate. Combined organics were dried over magnesium sulfate, filtered,concentrated in vacuo, and purified via reverse phase HPLC (10-42%acetonitrile/water gradient, 0.05% trifluoroacetic acid modifier) toafford the title compound. ¹H NMR (600 MHz, CDCl₃) δ 9.00 (d, 1H); 8.55(d, 1H); 8.23 (d, 1H); 7.91 (s, 1H); 7.80 (s, 1H); 7.76 (dd, 1H); 7.60(d, 1H); 7.34 (d, 1H); 7.23 (d, 1H); 4.95 (d, 1H); 3.98 (s, 3H);3.56-3.51 (m, 4H); 2.78-2.53 (m, 6H); 1.46 (s, 9H). Hydroxyl proton wasnot observed. LRMS (APCI) calc'd for (C₂₉H₃₄N₅O₄) [M+H]+, 516.3; found516.3.

Example 73

7-(1-hydroxy-2-piperazin-1-ylethyl)-3-(1-methyl-1H-pyrazol-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one(Compound 347)

tert-butyl4-{2-hydroxy-2-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]ethyl}piperazine-1-carboxylate(30 mg, 0.058 mmol) was dissolved in 0.5 mL of dichloromethane.Trifluroacetic acid (53 μL, 0.53 mmol) was added and the reaction wasstirred at room temperature for 8 hours. The resulting mixture wasconcentrated in vacuo and directly purified via reverse phase HPLC(10-100% acetonitrile/water gradient, 0.05% trifluoroacetic acidmodifier) to afford the title compound as the TFA salt. ¹H NMR (600 MHz,CD₃OD) δ 9.11 (d, 1H); 8.67 (d, 1H); 8.31 (d, 1H); 8.25 (s, 1H); 8.05(d, 1H); 7.83 (dd, 1H); 7.75 (d, 1H); 7.39 (d, 1H); 7.32 (d, 1H); 5.12(dd, 1H); 3.97 (s, 3H); 3.39-3.34 (m, 4H); 3.18-3.16 (m, 4H); 3.04-2.96(m, 2H). Hydroxyl and amine protons were not observed. LRMS (APCI)calc'd for (C₂₄H₂₆N₅O₂) [M+H]+, 416.2; found 416.2.

Example 74

N′-[11-Chloro-3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N,N-dimethylsulfamide(Compound 348)

N-Chlorosuccinimide (30.6 mg, 0.229 mmol) was added toN,N-dimethyl-N′-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]sulfamide(Compound 118) (75 mg, 0.183 mmol) suspended in acetonitrile (18.3 ml)at room temperature. The resulting suspension was heated to 100° C. in asealed vial for 24 h. After standing at room temperature for anadditional 2 days, the reaction was basified with aqueous sodiumhydrogen carbonate (saturated, 75 mL) and extracted with dichloromethane(2×50 mL). The combined organics were dried over anhydrous Na₂SO₄,filtered and concentrated under reduced pressure. The residue waspurified by preparative HPLC reverse phase (C-18), eluting withacetonitrile/water+0.1% TFA, to afford the title compound as ayellow/orange solid. ¹H NMR (600 MHz, CDCl₃) δ 9.10 (d, 1H, J=1.8 Hz);8.45 (d, 1H, J=2.4 Hz); 7.94 (d, 1H, J=0.6 Hz); 7.83 (s, 1H); 7.79 (d,1H, J=2.4 Hz); 7.68 (s, 1H); 7.55 (dd, 1H, J=8.4, 2.4 Hz); 7.50 (d, 1H,J=9.0 Hz); 7.03 (s, 1H); 4.00 (s, 3H); 2.91 (s, 6H). LCMS (APCI) exactmass calc'd for [M+H]⁺ (C₂₀H₁₈ClN₅O₃S) requires m/z 444.1 found 444.1.

Example 75

7-(2,2-difluoro-1-hydroxyethyl)-3-(1-methyl-1H-pyrazol-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one(Compound 349);7-(2,2-difluoro-1(R)-hydroxyethyl)-3-(1-methyl-1H-pyrazol-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one(Compound 349R); and7-(2,2-difluoro-1(S)-hydroxyethyl)-3-(1-methyl-1H-pyrazol-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one(Compound 349S) Step 1:3-chloro-7-iodo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one

A sealed tube was charged with3-chloro-7-bromo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one (1.0 g, 3.1mmol), CuI (59 mg, 0.31 mmol), and sodium iodide (0.94 g, 6.2 mmol). Thetube was evacuated and backfilled with argon three times. Fully degasseddioxane (8 mL) was added. The tube was sealed, placed in an oil bath at110° C., and stirred rapidly for 24 hours. Upon completion, the reactionmixture was cooled and quenched via the addition of 20 mL of a 30%aqueous ammonia solution, poured into 80 mL of water, and extractedthree times with 150 mL dichloromethane. The combined organic phaseswere dried over magnesium sulfate, filtered, concentrated in vacuo, andpurified via flash chromatography (silica, 0-100% ethyl acetate/hexanes)to afford the title compound. ¹H NMR (600 MHz, d6-DMSO) δ 8.99 (d, 1H),8.43 (d, 1H), 8.39 (d, 1H), 8.16 (dd, 1H), 7.60 (d, 1H), 7.42 (d, 1H),7.32 (d, 1H). LRMS (APCI) calc'd for (C₁₄H₈ClINO) [M+H]+, 367.9; found367.9.

Step 2:3-chloro-7-{2,2-difluoro-1-[(2-methoxyethoxy)methoxy]vinyl}-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one

A sealed tube was charged with3-chloro-7-iodo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one (0.40 g, 1.1mmol), CuI (41 mg, 0.22 mmol), Pd(OAc)₂ (6 mg, 0.03 mmol), andtriphenylphosphine (30 mg, 0.11 mmol). The tube was evacuated andbackfilled with argon three times. Fully degassed DMF (2.5 mL) was addedfollowed by the addition of9,9-dibutyl-8-(difluoromethylene)-2,5,7-trioxa-9-stannatridecane(prepared as outlined in Tetrahedron 1995, 51, 9201). The tube wassealed, placed in an oil bath at 50° C., and stirred for 19 hours. Thereaction mixture was then cooled and poured into a mixture of ethylacetate and water. The aqueous layer was extracted twice with ethylacetate and the combined organics were dried over magnesium sulfate,filtered, concentrated in vacuo, and purified via flash chromatography(silica, 0-50% ethyl acetate/hexanes) to afford the title compoundslightly contaminated with tributyltin residue. The mixture was taken upin dichloromethane (5 mL) and water (1 mL). Potassium fluoride (85 mg,1.5 mmol) was added and the biphasic mixture was vigorously stirred for2 hrs, at which point the reaction was diluted with water and extractedwith dichloromethane. The combined organics were dried over magnesiumsulfate, filtered, concentrated in vacuo, and purified via flashchromatography (silica, 0-50% ethyl acetate/hexanes) to afford the titlecompound. ¹H NMR (600 MHz, CD₃OD) δ 8.84 (d, 1H), 8.51 (d, 1H), 8.31 (s,1H), 7.85 (d, 1H), 7.76 (d, 1H), 7.38 (d, 1H), 7.31 (d, 1H), 4.93 (s,2H), 3.85 (t, 2H), 3.53 (t, 2H), 3.32 (s, 3H). LRMS (APCI) calc'd for(C₂₀H₁₇ClF₂NO₄) [M+H]+, 408.1; found 408.1.

Step 3:3-chloro-7-(difluoroacetyl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one

To a cooled (0° C.) solution of3-chloro-7-{2,2-difluoro-1-[(2-methoxyethoxy)methoxy]vinyl}-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one(50 mg, 0.12 mmol) in a mixture of methanol (0.6 mL) and dichloromethane(0.6 mL) was added chlorotrimethylsilane (0.08 mL, 0.61 mmol). Themixture was allowed to warm to ambient temperature and stirredovernight. The mixture was then poured into an aqueous sodiumbicarbonate solution and extracted with ethyl acetate three times. Thecombined organics were dried over magnesium sulfate, filtered,concentrated in vacuo, and purified via flash chromatography (silica,0-60% ethyl acetate/hexanes) to afford the title compound. ¹H NMR (600MHz, CD₃OD) δ 8.84 (d 1H), 8.52 (d, 1H), 8.41 (s, 1H), 7.93 (dd, 1H),7.76 (d, 1H), 7.42 (d, 1H), 7.33 (d, 1H), 5.79 (t, 1H). LRMS (APCI)calc'd for (C₁₆H₉ClF₂NO₂) [M+H]+, 320.0; found 320.0.

Step 4:3-chloro-7-(2,2-difluoro-1-hydroxyethyl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-ol

Sodium borohydride (15 mg, 0.4 mmol) was added to a slurry of3-chloro-7-(difluoroacetyl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one(60 mg, 0.19 mmol) in methanol (2 mL) at room temperature. The mixturewas stirred for 20 minutes at which time it was quenched via thedropwise addition of 2N aqueous hydrochloric acid. Once gas evolutionceased, the solvent was removed in vacuo. The resulting residue wastaken up in ethyl acetate and poured into saturated aqueous sodiumbicarbonate. The aqueous layer was extracted with ethyl acetate threetimes. The combined organics were dried over magnesium sulfate,filtered, concentrated in vacuo, and purified via flash chromatography(silica, 0-50% ethyl acetate/hexanes) to afford the title compound. ¹HNMR (600 MHz, CD₃OD) δ 8.37 (s, 1H), 8.14 (s, 1H), 7.87 (d, 1H), 7.36(m, 3H), 7.15 (dd, 1H), 5.82 (tt, 1H), 5.19 (s, 1H), 4.83-4.78 (m, 1H),3.30 (s, 2H).

Step 5:3-chloro-7-(2,2-difluoro-1-hydroxyethyl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one

Manganese dioxide (0.16 g, 1.9 mmol) was added to a solution of3-chloro-7-(2,2-difluoro-1-hydroxyethyl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-ol(60 mg, 0.19 mmol) in ethyl acetate (2 mL) and the mixture was stirredat room temperature for 8 hours. The slurry was then filtered throughcelite, eluting with ethyl acetate. The filtrate was concentrated invacuo, and purified via flash chromatography (silica, 0-50% ethylacetate/hexanes) to afford the title compound. ¹H NMR (600 MHz, CD₃OD) δ8.75 (d, 1H), 8.39 (d, 1H), 8.25 (d, 1H), 7.81 (dd, 1H), 7.65 (d, 1H),7.29 (d, 1H), 7.19 (d, 1H), 5.89 (dt, 1H), 4.93 (dt, 1H). Hydroxylproton was not observed.

Step 6:7-(2,2-difluoro-1-hydroxyethyl)-3-(1-methyl-1H-pyrazol-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one(Compound 349);7-(2,2-difluoro-1(R)-hydroxyethyl)-3-(1-methyl-1H-pyrazol-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one(Compound 349R); and7-(2,2-difluoro-1(S)-hydroxyethyl)-3-(1-methyl-1H-pyrazol-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one(Compound 349S)

A sealed tube was charged with3-chloro-7-(2,2-difluoro-1-hydroxyethyl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one(42 mg, 0.13 mmol),1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (54mg, 0.26 mmol), Pd₂(dba)₃ (6 mg, 0.007 mmol), (tBu)₃PBF₄ (4 mg, 0.013mmol), and potassium fluoride (23 mg, 0.39 mmol). The tube was evacuatedand backfilled with argon three times. Fully degassed DMF (1.0 mL) wasadded and the tube was sealed, placed in an oil bath at 95° C., andstirred for 4 hours. The reaction mixture was then cooled and pouredinto a mixture of ethyl acetate and brine. The aqueous layer wasextracted twice with ethyl acetate and the combined organics were driedover magnesium sulfate, filtered, concentrated in vacuo. Purificationvia reverse phase HPLC (10-100% acetonitrile/water gradient, 0.05%trifluoroacetic acid modifier) afforded the title compound. The twoenantiomers were separated via preparative chiral HPLC (OJ column, 65%ethanol/heptane isocratic).

Enantiomer A: ¹H NMR (600 MHz, CDCl₃) δ 9.01 (d, 1H), 8.57 (m, 1H), 8.32(s, 1H), 7.91 (s, 1H), 7.82 (s, 1H), 7.78 (d, 1H), 7.64 (d, 1H),7.42-7.39 (m, 1H), 7.24-7.23 (m, 1H), 5.84 (dt, 1H), 5.04-5.00 (m, 1H),4.0 (s, 3H). Hydroxyl proton was not observed. LRMS (APCI) calc'd for(C₂₀H₁₆F₂N₃O₂) [M+H]+, 368.1; found 368.0. τ_(R): 12.5 min (analyticalchiral HPLC, OJ column, 0.46 cm×25 cm, 65% ethanol/heptane, isocratic,flow rate=0.75 mL/min).

Enantiomer B: ¹H NMR and LRMS data matched Enantiomer A. τ_(R): 17.0 min(analytical chiral HPLC, OJ column, 0.46 cm×25 cm, 65% ethanol/heptane,isocratic, flow rate=0.75 mL/min).

Example 76

N-(1,4-dioxan-2-ylmethyl)-N′-[6-fluoro-3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-methylsulfamide(Compound 350) Step 1: 6-bromo-2-fluoro-3-methoxybenzaldehyde

To a stirred solution of LDA (62 mmol) in THF (100 mL) was added4-bromo-2-fluoro-1-methoxybenzene (12 g, 59 mmol) in THF (20 mL) slowlyat −78° C. The reaction mixture was left to stir at −78 C for 2 h,treated with DMF (15 g, 210 mmol) in THF (20 mL) slowly, left to stir at−78 C for 1 h, and allowed to warm to room temperature as the bath did.The reaction mixture was treated with water and extracted with EtOAc(×3). The combined organics were washed with brine, dried (Na₂SO₄),concentrated, and purified by flash chromatography to afford the titlecompound. ¹H NMR (600 MHz, CDCl₃) δ 10.34 (s, 1H); 7.39 (dd, 1H); 7.04(t, 1H); 3.92 (s, 3H).

Step 2: 2-fluoro-3-methoxy-6-vinylbenzaldehyde

To a stirred solution of 6-bromo-2-fluoro-3-methoxybenzaldehyde (13 g,56 mmol) in nPrOH (200 mL) were added potassium vinyltrifluoroborate(7.9 g, 59 mmol), PdCl₂(dppf) (0.91 g, 1.1 mmol), and TEA (7.8 mL, 56mmol). The reaction mixture was purged with N₂ for 10 min, heated toreflux for 3 h, cooled to room temperature, treated with water, andconcentrated. The residue was extracted with EtOAc (×3). The combinedorganics were washed with brine, dried (Na₂SO₄), concentrated, andpurified by flash chromatography to afford the title compound. ¹H NMR(600 MHz, CDCl₃) δ 10.53 (s, 1H); 7.43 (dd, 1H); 7.31 (d, 1H); 7.16 (t,1H); 5.60 (d, 1H); 5.36 (d, 1H); 3.95 (s, 3H).

Step 3:(2,5-dichloropyridin-3-yl)(2-fluoro-3-methoxy-6-vinylphenyl)methanol

To a stirred solution of nBuLi (1.6 M in hexane, 29.0 mL, 46.4 mmol) indiisopropyl ether (80 mL) was added 3-bromo-2,5-dichloropyridine (10.5g, 46.4 mmol) in diisopropylether (60 mL) slowly at −78° C. Theresulting suspension was treated with2-fluoro-3-methoxy-6-vinylbenzaldehyde (7.6 g, 42.2 mmol) indiisopropylether (60 mL) and benzene (3 mL), and allowed to stir at −78°C. for 30 min followed by warming to room temperature as the bath did.The mixture was treated with saturated NH₄Cl solution and extracted withEtOAc (×3). The combined organics were washed with brine, dried(Na₂SO₄), concentrated, and purified by flash chromatography to affordthe title compound.

Step 4:(2,5-dichloropyridin-3-yl)(2-fluoro-3-methoxy-6-vinylphenyl)methanone

To a stirred solution of(2,5-dichloropyridin-3-yl)(2-fluoro-3-methoxy-6-vinylphenyl)methanol(11.6 g, 35.3 mmol) in CH₂Cl₂ (400 mL) was added MnO₂ (80 g, 920 mmol).The reaction mixture was allowed to stir overnight, filtered through apad of Celite, and concentrated to afford the title compound. LRMS (ESI)calc'd for (C₁₅H₁₀Cl₂FNO₂) [M+H]⁺, 326.0; found 326.0.

Step 5:(5-chloro-2-vinylpyridin-3-yl)(2-fluoro-3-methoxy-6-vinylphenyl)methanone

To a stirred solution of(2,5-dichloropyridin-3-yl)(2-fluoro-3-methoxy-6-vinylphenyl)methanone(11.6 g, 35.6 mmol) in nPrOH (200 mL) were added potassiumvinyltrifluoroborate (5.00 g, 37.3 mmol), PdCl₂(dppf) (580 mg, 0.71mmol), and TEA (4.96 mL, 35.6 mmol). The reaction mixture was purgedwith N₂ for 10 min, heated to reflux for 3 h, cooled to roomtemperature, treated with water, and concentrated. The residue wasextracted with EtOAc (×3). The combined organics were washed with brine,dried (Na₂SO₄), concentrated, and purified by flash chromatography toafford the title compound. ¹H NMR (600 MHz, CDCl₃) δ 8.63 (d, 1H); 7.62(d, 1H); 7.41 (d, 1H); 7.36 (dd, 1H); 7.09 (t, 1H); 6.57 (dd, 1H); 6.54(d, 1H); 5.63 (m, 2H); 5.23 (d, 1H); 3.92 (s, 3H). LRMS (ESI) calc'd for(C₁₇H₁₃ClFNO₂) [M+H]+, 318.1; found 318.1.

Step 6:3-chloro-6-fluoro-7-methoxy-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one

To a stirred solution of(5-chloro-2-vinylpyridin-3-yl)(2-fluoro-3-methoxy-6-vinylphenyl)methanone(6.20 g, 19.5 mmol) in toluene (1 L) was added Zhan IB catalyst (2.0 g,2.8 mmol). The reaction mixture was purged with N₂ for 20 min, heated toreflux overnight, cooled to room temperature, concentrated, and purifiedby flash chromatography to afford the title compound. LRMS (ESI) calc'dfor (C₁₅H₉ClFNO₂) [M+H]+, 290.0; found 290.0.

Step 7:3-chloro-6-fluoro-7-hydroxy-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one

To a stirred solution of3-chloro-6-fluoro-7-methoxy-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one(2.0 g, 6.9 mmol) in CH₂Cl₂ (100 mL) was added BBr₃ (1 M in CH₂Cl₂, 27.6mL, 27.6 mmol) at −78° C. The mixture was allowed to warm to roomtemperature as the bath did. After 6 h at room temperature, the mixturewas cooled to 0° C. and treated with aqueous NaHCO₃ solution. The yellowprecipitate was filtered, washed with CH₂Cl₂, and dried underhigh-vacuum overnight to afford the title compound. ¹H NMR (600 MHz,CD₃SOCD₃) δ 8.93 (d, 1H); 8.28 (d, 1H); 7.46 (d, 1H); 7.37 (d, 1H); 7.33(t, 1H); 7.08 (d, 1H). LRMS (ESI) calc'd for (C₁₄H₇ClFNO₂) [M+H]⁺,276.0; found 276.0.

Step 8:3-chloro-6-fluoro-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yltrifluoromethanesulfonate

To a stirred solution of3-chloro-6-fluoro-7-hydroxy-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one(1.0 g, 3.6 mmol) and cesium carbonate (1.3 g, 4.0 mmol) in DMF (20 mL)was added N-phenyltrifluoromethanesulfonimide (1.4 g, 4.0 mmol) at 0° C.The reaction mixture was left to stir at 0° C. for 20 min, treated withaqueous NaHCO₃ solution, diluted with CH₂Cl₂, and washed with water(×3). The organic layer was washed with brine, dried (Na₂SO₄),concentrated, and purified by flash chromatography to afford the titlecompound. ¹H NMR (600 MHz, CDCl₃) δ 8.83 (d, 1H); 8.26 (d, 1H); 7.59(dd, 1H); 7.45 (d, 1H); 7.36 (d, 1H); 7.23 (d, 1H). LRMS (ESI) calc'dfor (C₁₅H₆ClF₄NO₄S) [M+H]⁺, 408.0; found 407.9.

Step 9:N′-(3-chloro-6-fluoro-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)-N-(1,4-dioxan-2-ylmethyl)-N-methylsulfamide

To a stirred solution of3-chloro-6-fluoro-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yltrifluoromethanesulfonate (200 mg, 0.49 mmol) in 1,4-dioxane (7 mL) wereadded N-(1,4-dioxan-2-ylmethyl)-N-methylsulfamide (200 mg, 0.98 mmol),Pd2(dba)₃ (68 mg, 0.074 mmol), Xantphos (85 mg, 0.15 mmol), and K3PO4(280 mg, 1.3 mmol). The reaction mixture was purged with N2 for 5 min,heated to 110° C. 8 h, cooled to room temperature, diluted with water,and extracted with CH₂Cl₂ (×3). The combined organics were dried(Na2SO4), concentrated, and purified by flash chromatography to affordthe title compound. ¹H NMR (600 MHz, CDCl₃) δ 8.78 (d, 1H); 8.24 (d,1H); 7.99 (d, 1H); 7.93 (t, 1H); 7.36 (d, 1H); 7.21 (br s, 2H);3.64-4.00 (series of m, 7H); 3.36 (dd, 1H); 3.08 (dd, 1H); 2.99 (s, 3H).LRMS (ESI) calc'd for (C20H19ClFN3O5S) [M+H]+, 468.1; found 468.0.

Step 10:N-(1,4-dioxan-2-ylmethyl)-N′-[6-fluoro-3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-methylsulfamide

To a stirred solution ofN′-(3-chloro-6-fluoro-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)-N-(1,4-dioxan-2-ylmethyl)-N-methylsulfamide(127 mg, 0.271 mmol) in DMF (7 mL) were added1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(113 mg, 0.543 mmol), tri-t-butylphosphonium tetraflroroborate (16 mg,0.054 mmol), potassium fluoride (52 mg, 0.896 mmol), and Pd₂(dba)₃ (25mg, 0.027 mmol). The reaction mixture was purged with N₂ for 5 min,heated to 130 C for 9 h, cooled to room tempearture, treated with water,and extracted with CH₂Cl₂ (×3). The combined organics were dried(Na₂SO₄), concentrated, and purified by prep-HPLC to afford the titlecompound. ¹H NMR (600 MHz, CDCl₃) δ 8.99 (d, 1H); 8.31 (d, 1H); 7.91 (s,1H); 7.90 (m, 2H); 7.81 (s, 1H); 7.36 (d, 1H); 7.26 (d, 1H); 7.17 (d,1H); 4.00 (s, 3H); 3.64-4.00 (series of m, 7H); 3.36 (dd, 1H); 3.09 (dd,1H); 2.99 (s, 3H). LRMS (ESI) calc'd for (C₂₄H₂₄FN₅O₅S) [M+H]+, 514.1;found 514.1.

The following compounds were made according to Scheme 8, but using theappropriate methoxybenzene in Step 1: TABLE 7 MS Comp. Structure Name(M + 1) 351

N-(1,4-dioxan-2-ylmethyl)- N′-[8-fluoro-3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H- benzo[4,5]cyclohepta[1,2- b]pyridin-7-yl]-N-methylsulfamide calc'd [M + H]⁺, 514.1; found 514.1. 352

6-fluoro-7-(2-fluoro-1- hydroxyethyl)-3-(1- methyl-1H-pyrazol-4-yl)- 5H-benzo[4,5]cyclohepta[1,2- b]pyridin-5-one calc'd [M + H]⁺, 368.1; found368.1.

1. A compound of Formula I:

or pharmaceutically acceptable salts thereof, wherein: a dashed linerepresents an optional double bond; a is independently 0 or 1; b isindependently 0 or 1; m is independently 0, 1, or 2; R¹ is selected fromhalogen, aryl, heterocyclyl, —C(═O)NR¹⁰R¹¹, (C═O)OC₁-C₆ alkyl andNR¹⁰R¹¹; said alkyl, aryl and heterocyclyl group optionally substitutedwith one to five substituents, each substituent independently selectedfrom R⁸; R² and R³ are independently selected from hydrogen, OH, —O—C₁₋₆alkyl, —O—C(═O)C₁₋₆ alkyl, —O-aryl and NR¹⁰R¹¹, each alkyl and aryloptionally substituted with one to five substituents, each substituentindependently selected from R⁸; or R² and R³ are combined to form ═O or═N—OR^(c); R⁴, R⁶ and R⁷ are each independently hydrogen, halogen,C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, OH, —O—C₁₋₆alkyl, —O—C(═O)C₁₋₆alkyl, —O-aryl, S(O)_(m)R^(a) and NR¹⁰R¹¹, each alkyl and aryloptionally substituted with one to five substituents, each substituentindependently selected from R⁸; R⁵ is selected from hydrogen, C₁₋₆alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, OH, —O—C₁₋₆alkyl, —O—C(═O)C₁₋₆ alkyl,—O-aryl, S(O)_(m)R^(a), —C(═O)NR¹⁰R¹¹, —NHS(O)₂NR¹⁰R¹¹ and NR¹⁰R¹¹, eachalkyl, alkenyl, alkynyl and aryl optionally substituted with one to fivesubstituents, each substituent independently selected from R⁸; providedthat at least one of R⁴, R⁵ and R⁶ is not hydrogen; R⁸ independentlyis: 1) (C═O)_(a)O_(b)C₁-C₁₀ alkyl, 2) (C═O)_(a)O_(b)aryl, 3) C₂-C₁₀alkenyl, 4) C₂-C₁₀ alkynyl, 5) (C═O)_(a)O_(b) heterocyclyl, 6) CO₂H, 7)halo, 8) CN, 9) OH, 10) O_(b)C₁-C₆ perfluoroalkyl, 11)O_(a)(C═O)_(b)NR¹⁰R¹¹, 12) S(O)_(m)R^(a), 13) S(O)₂NR¹⁰R¹¹, 14)OS(═O)R^(a), 15) oxo, 16) CHO, 17) (N═O)R¹⁰R¹¹, 18) (C═O)_(a)O_(b)C₃-C₈cycloalkyl, 19) O_(b)SiR^(a) ₃, or 20) NO₂; said alkyl, aryl, alkenyl,alkynyl, heterocyclyl, and cycloalkyl optionally substituted with one,two or three substituents selected from R⁹; two R⁸s, attached to thesame carbon atom are combined to form —(CH₂)_(u)— wherein u is 3 to 6and one or two of the carbon atoms is optionally replaced by a moietyselected from O, S(O)_(m), —N(R^(a))C(O)—, —N(R^(b))— and —N(COR^(a))—;R⁹ is independently selected from: 1) (C═O)_(a)O_(b)(C₁-C₁₀)alkyl, 2)O_(b)(C₁-C₃)perfluoroalkyl, 3) oxo, 4) OH, 5) halo, 6) CN, 7)(C₂-C₁₀)alkenyl, 8) (C₂-C₁₀)alkynyl, 9) (C═O)_(a)O_(b)(C₃-C₆)cycloalkyl,10) (C═O)_(a)O_(b)(C₀-C₆)alkylene-aryl, 11)(C═O)_(a)O_(b)(C₀-C₆)alkylene-heterocyclyl, 12)(C═O)_(a)O_(b)(C₀-C₆)alkylene-N(R^(b)) 13) C(O)R^(a), 14)(C₀-C₆)alkylene-CO₂R^(a), 15) C(O)H, 16) (C₀-C₆)alkylene-CO₂H, and 17)C(O)N(R^(b))₂, 18) S(O)_(m)R^(a), and 19) S(O)₂NR¹⁰R¹¹; said alkyl,alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl is optionallysubstituted with one, two or three substituents selected from R^(b), OH,(C₁-C₆)alkoxy, halogen, CO₂H, CN, O(C═O)C₁-C₆ alkyl, oxo, and N(R^(b))₂;or two R⁹s, attached to the same carbon atom are combined to form—(CH₂)_(u)— wherein u is 3 to 6 and one or two of the carbon atoms isoptionally replaced by a moiety selected from O, S(O)_(m),—N(R^(a))C(O)—, —N(R^(b))— and —N(COR^(a))—; R¹⁰ and R¹¹ areindependently selected from: 1) H, 2) (C═O)O_(b)C₁-C₁₀ alkyl, 3)(C═O)O_(b)C₃-C₈ cycloalkyl, 4) (C═O)O_(b)aryl, 5)(C═O)O_(b)heterocyclyl, 6) C₁-C₁₀ alkyl, 7) aryl, 8) C₂-C₁₀ alkenyl, 9)C₂-C₁₀ alkynyl, 10) heterocyclyl, 11) C₃-C₈ cycloalkyl, 12) SO₂R^(a),and 13) (C═O)NR^(b) ₂, said alkyl, cycloalkyl, aryl, heterocylyl,alkenyl, and alkynyl is optionally substituted with one, two or threesubstituents selected from R⁸, or R¹⁰ and R¹¹ can be taken together withthe nitrogen to which they are attached to form a monocyclic or bicyclicheterocycle with 5-7 members in each ring and optionally containing, inaddition to the nitrogen, one or two additional heteroatoms selectedfrom N, O and S, said monocyclic or bicyclic heterocycle optionallysubstituted with one, two or three substituents selected from R⁹; R^(a)is independently selected from: (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₃-C₆)cycloalkyl, aryl, —(C₁-C₆)alkylenearyl, heterocyclyl and—(C₁-C₆)alkyleneheterocyclyl; R^(b) is independently selected from: H,(C₁-C₆)alkyl, aryl, —(C₁-C₆)alkylenearyl, heterocyclyl,—(C₁-C₆)alkyleneheterocyclyl, (C₃-C₆)cycloalkyl, (C═O)OC₁-C₆ alkyl,(C═O)C₁-C₆ alkyl or S(O)₂R^(a); and R^(C) is independently selectedfrom: H, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₃-C₆)cycloalkyl, aryl,—(C₁-C₆)alkylenearyl, heterocyclyl and —(C₁-C₆)alkyleneheterocyclyl; butexcluding compounds represented by the following exclusion table (R^(7a)and R^(7b) are H): R¹ R² R³ R⁴ R⁵ R⁶ R⁷ Dashed line Ph Form ═O H H H Brdouble bond Ph Form ═O H H H H double bond Ph Form ═O H Br H H doublebond Ph Form ═O H H H Cl double bond Cl Form ═O H H H Br double bond PhH OH H H H

double bond Ph Form ═O H H H

double bond Ph H H H H H oxazolyl absent


2. The compound according to claim 1 of the Formula II:

or pharmaceutically acceptable salts thereof, wherein a is independently0 or 1; b is independently 0 or 1; m is independently 0, 1, or 2; R¹ isselected from aryl, heterocyclyl and NR¹⁰R¹¹; said aryl and heterocyclylgroup optionally substituted with one to five substituents, eachsubstituent independently selected from R⁸; R⁴ and R⁶ are eachindependently hydrogen, halogen, C₁₋₆alkyl, OH, —O—C₁₋₆alkyl,—O—C(═O)C₁₋₆ alkyl, —O-aryl and NR¹⁰R¹¹, each alkyl and aryl optionallysubstituted with one to five substituents, each substituentindependently selected from R⁸; R⁵ is selected from hydrogen, C₁₋₆alkyl,C₂₋₆ alkenyl, OH, —O—C₁₋₆alkyl, —O—C(═O)C₁₋₆ alkyl, —O-aryl,S(O)_(m)R^(a), —C(═O)NR¹⁰R¹¹, —NHS(O)₂NR¹⁰R¹¹ and NR¹⁰R¹¹, each alkyl,alkenyl and aryl optionally substituted with one to five substituents,each substituent independently selected from R⁸; provided that one ofR⁴, R⁵ and R⁶ are not hydrogen; R⁸ independently is: 1)(C═O)_(a)O_(b)C₁-C₁₀ alkyl, 2) (C═O)_(a)O_(b)aryl, 3) C₂-C₁₀ alkenyl, 4)C₂-C₁₀ alkynyl, 5) (C═O)_(a)O_(b) heterocyclyl, 6) CO₂H, 7) halo, 8) CN,9) OH, 10) O_(b)C₁-C₆ perfluoroalkyl, 11) O_(a)(C═O)_(b)NR¹⁰R¹¹, 12)S(O)_(m)R^(a), 13) S(O)₂NR¹⁰R¹¹, 14) OS(═O)R^(a), 15) oxo, 16) CHO, 17)(N═O)R¹⁰R¹¹, or 18) (C═O)_(a)O_(b)C₃-C₈ cycloalkyl, said alkyl, aryl,alkenyl, alkynyl, heterocyclyl, and cycloalkyl optionally substitutedwith one, two or three substituents selected from R⁹; or two R⁸s,attached to the same carbon atom are combined to form —(CH₂)_(u)—wherein u is 3 to 6 and one or two of the carbon atoms is optionallyreplaced by a moiety selected from O, S(O)_(m), —N(R^(a))C(O)—,—N(R^(b))— and —N(COR^(a))—; R⁹ is independently selected from: 1)(C═O)_(a)O_(b)(C₁-C₁₀)alkyl, 2) O_(b)(C₁-C₃)perfluoroalkyl, 3) oxo, 4)OH, 5) halo, 6) CN, 7) (C₂-C₁₀)alkenyl, 8) (C₂-C₁₀)alkynyl, 9)(C═O)_(a)O_(b)(C₃-C₆)cycloalkyl, 10) (C═O)_(a)O_(b)(C₀-C₆)alkylene-aryl,11) (C═O)_(a)O_(b)(C₀-C₆)alkylene-heterocyclyl, 12)(C═O)_(a)O_(b)(C₀-C₆)alkylene-N(R^(b))₂, 13) C(O)R^(a), 14)(C₀-C₆)alkylene-CO₂R^(a), 15) C(O)H, 16) (C₀-C₆)alkylene-CO₂H, and 17)C(O)N(R^(b))₂, 18) S(O)_(m)R^(a), and 19) S(O)₂NR¹⁰R¹¹; said alkyl,alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl is optionallysubstituted with one, two or three substituents selected from R^(b), OH,(C₁-C₆)alkoxy, halogen, CO₂H, CN, O(C═O)C₁-C₆ alkyl, oxo, and N(R^(b))₂;or R¹⁰ and R¹¹ are independently selected from: 1) H, 2)(C═O)O_(b)C₁-C₁₀ alkyl, 3) (C═O)O_(b)C₃-C₈ cycloalkyl, 4)(C═O)O_(b)aryl, 5) (C═O)O_(b)heterocyclyl, 6) C₁-C₁₀ alkyl, 7) aryl, 8)C₂-C₁₀ alkenyl, 9) C₂-C₁₀ alkynyl, 10) heterocyclyl, 11) C₃-C₈cycloalkyl, 12) SO₂R^(a), and 13) (C═O)NR^(b) ₂, said alkyl, cycloalkyl,aryl, heterocylyl, alkenyl, and alkynyl is optionally substituted withone, two or three substituents selected from R⁸, or R¹⁰ and R¹¹ can betaken together with the nitrogen to which they are attached to form amonocyclic or bicyclic heterocycle with 5-7 members in each ring andoptionally containing, in addition to the nitrogen, one or twoadditional heteroatoms selected from N, O and S, said monocyclic orbicyclic heterocycle optionally substituted with one, two or threesubstituents selected from R⁹; R^(a) is independently selected from:(C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₃-C₆)cycloalkyl, aryl,—(C₁-C₆)alkylenearyl, heterocyclyl and —(C₁-C₆)alkyleneheterocyclyl; andR^(b) is independently selected from: H, (C₁-C₆)alkyl, aryl,—(C₁-C₆)alkylenearyl, heterocyclyl, —(C₁-C₆)alkyleneheterocyclyl,(C₃-C₆)cycloalkyl, (C═O)OC₁-C₆ alkyl, (C═O)C₁-C₆ alkyl or S(O)₂R^(a). 3.The compound according to claim 2 of the Formula III:

or a pharmaceutically acceptable salt or stereoisomer thereof, wherein ais independently 0 or 1; b is independently 0 or 1; m is independently0, 1, or 2; R¹ is selected from aryl, heterocyclyl and NR¹⁰R¹¹; saidaryl and heterocyclyl group optionally substituted with one to fivesubstituents, each substituent independently selected from R⁸; R⁵ isselected from hydrogen, C₁₋₆alkyl, C₂₋₆ alkenyl, OH, —O—C₁₋₆alkyl,—O—C(═O)C₁₋₆ alkyl, —O-aryl, S(O)_(m)R^(a), —C(═O)NR¹⁰R¹¹,—NHS(O)₂NR¹⁰R¹¹ and NR¹⁰R¹¹, each alkyl, alkenyl and aryl optionallysubstituted with one to five substituents, each substituentindependently selected from R⁸; R⁸ independently is: 1)(C═O)_(a)O_(b)C₁-C₁₀ alkyl, 2) (C═O)_(a)O_(b)aryl, 3) C₂-C₁₀ alkenyl, 4)C₂-C₁₀ alkynyl, 5) (C═O)_(a)O_(b) heterocyclyl, 6) CO₂H, 7) halo, 8) CN,9) OH, 10) O_(b)C₁-C₆ perfluoroalkyl, 11) O_(a)(C═O)_(b)NR¹⁰R¹¹, 12)S(O)_(m)R^(a), 13) S(O)₂NR¹⁰R¹¹, 14) OS(═O)R^(a), 15) oxo, 16) CHO, 17)(N═O)R¹⁰R¹¹, or 18) (C═O)_(a)O_(b)C₃-C₈ cycloalkyl, said alkyl, aryl,alkenyl, alkynyl, heterocyclyl, and cycloalkyl optionally substitutedwith one, two or three substituents selected from R⁹; R⁹ isindependently selected from: 1) (C═O)_(a)O_(b)(C₁-C₁₀)alkyl, 2)O_(b)(C₁-C₃)perfluoroalkyl, 3) oxo, 4) OH, 5) halo, 6) CN, 7)(C₂-C₁₀)alkenyl, 8) (C₂-C₁₀)alkynyl, 9) (C═O)_(a)O_(b)(C₃-C₆)cycloalkyl,10) (C═O)_(a)O_(b)(C₀-C₆)alkylene-aryl, 11)(C═O)_(a)O_(b)(C₀-C₆)alkylene-heterocyclyl, 12)(C═O)_(a)O_(b)(C₀-C₆)alkylene-N(R^(b))₂, 13) C(O)R^(a), 14)(C₀-C₆)alkylene-CO₂R^(a), 15) C(O)H, 16) (C₀-C₆)alkylene-CO₂H, and 17)C(O)N(R^(b))₂, 18) S(O)_(m)R^(a), and 19) S(O)₂NR¹⁰R¹¹; said alkyl,alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl is optionallysubstituted with one, two or three substituents selected from R^(b), OH,(C₁-C₆)alkoxy, halogen, CO₂H, CN, O(C═O)C₁-C₆ alkyl, oxo, and N(R^(b))₂;R¹⁰ and R¹¹ are independently selected from: 1) H, 2) (C═O)O_(b)C₁-C₁₀alkyl, 3) (C═O)O_(b)C₃-C₈ cycloalkyl, 4) (C═O)O_(b)aryl, 5)(C═O)O_(b)heterocyclyl, 6) C₁-C₁₀ alkyl, 7) aryl, 8) C₂-C₁₀ alkenyl, 9)C₂-C₁₀ alkynyl, 10) heterocyclyl, 11) C₃-C₈ cycloalkyl, 12) SO₂R^(a),and 13) (C═O)NR^(b) ₂, said alkyl, cycloalkyl, aryl, heterocylyl,alkenyl, and alkynyl is optionally substituted with one, two or threesubstituents selected from R⁸, or R¹⁰ and R¹¹ can be taken together withthe nitrogen to which they are attached to form a monocyclic or bicyclicheterocycle with 5-7 members in each ring and optionally containing, inaddition to the nitrogen, one or two additional heteroatoms selectedfrom N, O and S, said monocyclic or bicyclic heterocycle optionallysubstituted with one, two or three substituents selected from R⁹; R^(a)is independently selected from: (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₃-C₆)cycloalkyl, aryl, —(C₁-C₆)alkylenearyl, heterocyclyl and—(C₁-C₆)alkyleneheterocyclyl; and R^(b) is independently selected from:H, (C₁-C₆)alkyl, aryl, —(C₁-C₆)alkylenearyl, heterocyclyl,—(C₁-C₆)alkyleneheterocyclyl, (C₃-C₆)cycloalkyl, (C═O)OC₁-C₆ alkyl,(C═O)C₁-C₆ alkyl or S(O)₂R^(a).
 4. A compound selected from:7-bromo-3-chloro-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;6-bromo-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;8-bromo-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;3-chloro-7-[(2,4-dimethoxybenzyl)amino]-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;7-amino-3-chloro-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;N-(3-chloro-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)methanesulfonamide;6-(methylthio)-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;6-(methylsulfonyl)-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;Methyl5-oxo-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-7-carboxylate;6-methyl-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;3-phenyl-7-[(trimethylsilyl)ethynyl]-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;3-phenyl-7-vinyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;7-ethyl-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;N-(5-oxo-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)acetamide;3-chloro-7-hydroxy-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;7-[(2,4-dimethoxybenzyl)amino]-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;6-amino-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;7-amino-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;8-amino-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;9-amino-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;2-hydroxy-N-(5-oxo-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)propanamide;3-phenyl-7-(pyridin-2-ylamino)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;7-[(3-methoxypropyl)amino]-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;7-[(2-methoxyethyl)amino]-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;7-[(3-methoxypropyl)amino]-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-ol;7-[(2-methoxyethyl)amino]-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;3-phenyl-7-[(2,2,2-trifluoroethyl)amino]-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;5-oxo-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-7-carboxylic acid;N-methyl-5-oxo-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-7-carboxamide;7-methyl-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;8-methyl-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;9-methyl-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;7-ethynyl-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;3-phenyl-7-[(1E/Z)-prop-1-en-1-yl]-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;3-phenyl-7-propyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;7-isobutyl-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;9-(methylthio)-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;7-(methylthio)-3-phenyl-10,11-dihydro-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;9-(methylsulfonyl)-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;6-methoxy-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;N-(5-oxo-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)methanesulfonamide;N′-(3-chloro-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)-N,N-dimethylsulfamide;N-benzyl-N′-(3-chloro-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)-N-methylsulfamide;N-(3-chloro-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)-1,1,1-trifluoromethanesulfonamide;3-chloro-7-([(3-methylpyridin-4-yl)methyl]amino}-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;N′-(3-chloro-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)-N-(isoxazol-3-ylmethyl)-N-methylsulfamide;N-(3-chloro-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)-N′-[(1-morpholin-4-ylcyclopentyl)methyl]sulfamide;3,7-bis[(pyridin-3-ylmethyl)amino]-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;3-chloro-7-[(pyridin-2-ylmethyl)amino]-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;N-[5-oxo-3-(3-thienyl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;7-[(2,4-dimethoxybenzyl)amino]-3-(1-methyl-1H-pyrazol-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;7-(isopropylamino)-3-(1-methyl-1H-pyrazol-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;3-chloro-7-{[(3-methylpyridin-2-yl)methyl]amino}-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;3-(1-methyl-1H-pyrazol-4-yl)-7-{[(3-methylpyridin-2-yl)methyl]amino}-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;N′-(3-chloro-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)-N-(1,4-dioxan-2-ylmethyl)-N-methylsulfamide;N-(1,4-dioxan-2-ylmethyl)-N-methyl-N′-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]sulfamide;N-[3-(4-chlorophenyl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;N-[3-(2-chlorophenyl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;N-(5-oxo-3-pyridin-4-yl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)methanesulfonamide;N-(5-oxo-3-pyridin-3-yl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)methanesulfonamide;N-[5-oxo-3-(1H-pyrazol-3-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;N-[3-(3-chlorophenyl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;N-(5-oxo-3-pyrimidin-5-yl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)methanesulfonamide;N-(5-oxo-3-quinolin-6-yl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)methanesulfonamide;N-[3-(3-furyl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;N-[3-(2-furyl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;N-[3-(4-fluorophenyl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;N-[3-(3-fluorophenyl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;N-[3-(2-fluorophenyl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;N-(5-oxo-3-quinolin-8-yl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)methanesulfonamide;N-(5-oxo-3-quinolin-3-yl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)methanesulfonamide;N-(5-oxo-3-quinolin-5-yl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)methanesulfonamide;N-[3-(2,4-dichlorophenyl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;N-(3-imidazo[1,2-a]pyrazin-3-yl-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)methanesulfonamide;N-[5-oxo-3-(1,3-thiazol-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;N-(3-isothiazol-4-yl-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)methanesulfonamide;N-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;N-(3-isothiazol-5-yl-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)methanesulfonamide;N-[3-(3,5-dimethylisoxazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;N-[5-oxo-3-(1H-pyrazol-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;methyl(4-{7-[(methylsulfonyl)amino]-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-3-yl}-1H-pyrazol-1-yl)acetate;ethyl3-(4-{7-[(methylsulfonyl)amino]-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-3-yl}-1H-pyrazol-1-yl)propanoate;N-(3-{1-[2-(dimethylamino)ethyl]-1H-pyrazol-4-yl}-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)methanesulfonamide;N-[3-(1-isobutyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;N-[5-oxo-3-(1-propyl-1H-pyrazol-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;N-(3-{1-[3-(dimethylamino)propyl]-1H-pyrazol-4-yl}-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)methanesulfonamide;N-{3-[1-(2-morpholin-4-yl-2-oxoethyl)-1H-pyrazol-4-yl]-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl}methanesulfonamide;N-{5-oxo-3-[1-(2-pyrrolidin-1-ylethyl)-1H-pyrazol-4-yl]-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl}methanesulfonamide;N-[3-(1-benzyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;(4-{7-[(methylsulfonyl)amino]-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-3-yl}-1H-pyrazol-1-yl)aceticacid;3-(4-{7-[(methylsulfonyl)amino]-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-3-yl}-1H-pyrazol-1-yl)propanoicacid;N-(3-{7-[(methylsulfonyl)amino]-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-3-yl}phenyl)-3-piperidin-1-ylpropanamide;N-(4-{7-[(methylsulfonyl)amino]-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-3-yl}phenyl)methanesulfonamide;N-(3-{1-[3-(benzyloxy)propyl]-1H-pyrazol-4-yl}-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)methanesulfonamide;N-[3-(1-isopropyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;N-{3-[1-(3-methylbutyl)-1H-pyrazol-4-yl]-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl}methanesulfonamide;N-[3-(1-cyclopentyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;N-{3-[1-(3-hydroxypropyl)-1H-pyrazol-4-yl]-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl}methanesulfonamide;3-{7-[(methylsulfonyl)amino]-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-3-yl}benzoicacid;3-(2,3-dihydro-1H-pyrazolo[1,2-a]pyrazol-4-ium-6-yl)-7-[(methylsulfonyl)amino]-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridiniumbis(trifluoroacetate); methyl2-(4-{7-[(methylsulfonyl)amino]-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-3-yl}-1H-pyrazol-1-yl)propanoate;N-{3-[1-(3,3-dimethyl-2-oxobutyl)-1H-pyrazol-4-yl]-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl}methanesulfonamide;4-{7-[(methylsulfonyl)amino]-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-3-yl}benzoicacid;N-[3-(3-nitrophenyl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;N-[3-(4-nitrophenyl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;N-isobutyl-3-{7-[(methylsulfonyl)amino]-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-3-yl}benzamide;3-{7-[(methylsulfonyl)amino]-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-3-yl}-N-(2-morpholin-4-ylethyl)benzamide;N-[2-(1-methylpyrrolidin-2-yl)ethyl]-3-{7-[(methylsulfonyl)amino]-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-3-yl}benzamide;N-[(1-methyl-1H-pyrazol-4-yl)methyl]-3-{7-[(methylsulfonyl)amino]-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-3-yl}benzamide;N-{3-[1-(3-hydroxypropyl)-1H-pyrazol-4-yl]-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl}methanesulfonamide;N-[(5-methylpyrazin-2-yl)methyl]-3-{7-[(methylsulfonyl)amino]-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-3-yl}benzamide;N-isobutyl-4-{7-[(methylsulfonyl)amino]-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-3-yl}benzamide;N-[(1-methyl-1H-pyrazol-4-yl)methyl]-4-{7-[(methylsulfonyl)amino]-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-3-yl}benzamide;2-methyl-N-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]propane-2-sulfonamide;N,N-dimethyl-N′-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]sulfamide;N-benzyl-N-methyl-N′-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]sulfamide;N,N-diethyl-N′-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]sulfamide;N-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]pyrrolidine-1-sulfonamide;N-ethyl-N-methyl-N′-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]sulfamide;N,N-dimethyl-N′-[5-oxo-3-(1-propyl-1H-pyrazol-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]sulfamide;N,N-dimethyl-N′-{3-[1-(2-morpholin-4-yl-2-oxoethyl)-1H-pyrazol-4-yl]-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl}sulfamide;N′-(3-{1-[3-(dimethylamino)propyl]-1H-pyrazol-4-yl}-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)-N,N-dimethylsulfamide;N-isopropyl-N-methyl-N′-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]sulfamide;7-(5-methyl-1,1-dioxido-1,2,5-thiadiazolidin-2-yl)-3-(1-methyl-1H-pyrazol-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;N-methyl-N′-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]sulfamide;1,1,1-trifluoro-N-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;7-[(2,4-dimethoxybenzyl)amino]-3-(3-thienyl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;7-[(2,4-dimethoxybenzyl)amino]-3-(1H-pyrazol-3-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;7-[(2,4-dimethoxybenzyl)amino]-3-(5-methyl-2-thienyl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;3-(1-benzothien-3-yl)-7-[(2,4-dimethoxybenzyl)amino]-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;N-(4-{7-[(2,4-dimethoxybenzyl)amino]-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-3-yl}phenyl)acetamide;4-{7-[(2,4-dimethoxybenzyl)amino]-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-3-yl}benzoicacid; 7-amino-3-(3-thienyl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;7-amino-3-(2-thienyl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;7-amino-3-(1H-pyrazol-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;7-amino-3-(1-methyl-1H-pyrazol-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;7-amino-3-(1H-pyrazol-3-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;7-amino-3-(5-methyl-2-thienyl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;7-amino-3-(1-benzothien-3-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;N-[4-(7-amino-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-3-yl)phenyl]acetamide;4-(7-amino-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-3-yl)benzoicacid;7-hydroxy-3-(3-thienyl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;7-[(cyclohexylmethyl)amino]-3-(1-methyl-1H-pyrazol-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;7-[(4-fluorobenzyl)amino]-3-(1-methyl-1H-pyrazol-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;3-(1-methyl-1H-pyrazol-4-yl)-7-vinyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;7-[(2,4-difluorobenzyl)amino]-3-(1-methyl-1H-pyrazol-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;3-(1-methyl-1H-pyrazol-4-yl)-7-[(2-phenylethyl)amino]-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;7-[(3,4-difluorobenzyl)amino]-3-(1-methyl-1H-pyrazol-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;7-[(4-methylbenzyl)amino]-3-(1-methyl-1H-pyrazol-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;7-[(2,4-dimethylbenzyl)amino]-3-(1-methyl-1H-pyrazol-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;7-{[2-(4-fluorophenyl)ethyl]amino}-3-(1-methyl-1H-pyrazol-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;7-(butylamino)-3-(1-methyl-1H-pyrazol-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;3-(1-methyl-1H-pyrazol-4-yl)-7-(propylamino)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;7-[(3-methylbutyl)amino]-3-(1-methyl-1H-pyrazol-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;7-(isopropylamino)-3-(1-methyl-1H-pyrazol-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;7-[(1,3-benzodioxol-5-ylmethyl)amino]-3-(1-methyl-1H-pyrazol-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;7-(isobutylamino)-3-(1-methyl-1H-pyrazol-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;7-[(2-methylbenzyl)amino]-3-(1-methyl-1H-pyrazol-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;3-(1-methyl-1H-pyrazol-4-yl)-7-{[2-(trifluoromethyl)benzyl]amino}-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;7-[(biphenyl-2-ylmethyl)amino]-3-(1-methyl-1H-pyrazol-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;7-[(2-chlorobenzyl)amino]-3-(1-methyl-1H-pyrazol-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;7-[(2,3-dimethylbenzyl)amino]-3-(1-methyl-1H-pyrazol-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;N-methyl-N′-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-(tetrahydrofuran-3-yl)sulfamide;N′-(3-{1-[3-(benzyloxy)propyl]-1H-pyrazol-4-yl}-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)-N,N-dimethylsulfamide;N′-{3-[1-(3-hydroxypropyl)-1H-pyrazol-4-yl]-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl}-N,N-dimethylsulfamide;7-[(imidazo[1,2-a]pyridin-3-ylmethyl)amino]-3-(1-methyl-1H-pyrazol-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;N,N-dimethyl-N′-(3-{1-[(3-methyloxetan-3-yl)methyl]-1H-pyrazol-4-yl}-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)sulfamide;7-{[(1-methyl-5-oxopyrrolidin-2-yl)methyl]amino}-3-(1-methyl-1H-pyrazol-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;3,7-bis(1-methyl-1H-pyrazol-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;3-(1-methyl-1H-pyrazol-4-yl)-7-(1H-pyrrol-2-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;3-(1-methyl-1H-pyrazol-4-yl)-7-{[(3-methylpyridin-4-yl)methyl]-amino}-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;3-(1-methyl-1H-pyrazol-4-yl)-7-(1H-pyrazol-3-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;N-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-2-(trifluoromethyl)benzamide;7-{[(1-ethylpyrrolidin-2-yl)methyl]amino}-3-(1-methyl-1H-pyrazol-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;7-[(2,6-dimethylbenzyl)amino]-3-(1-methyl-1H-pyrazol-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;N-methyl-N-[(1-methyl-5-oxopyrrolidin-2-yl)methyl]-N′-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]sulfamide;N-methyl-N-[(1-methyl-1H-imidazol-2-yl)methyl]-N′-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]sulfamide;N-methyl-N′-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-(tetrahydro-2H-pyran-2-ylmethyl)sulfamide;N-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-2-(trifluoromethyl)benzene-sulfonamide;N-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N′-[2-(trifluoromethyl)benzyl]sulfamide;methyl4-(7-{[(3-methylpyridin-2-yl)methyl]amino}-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-3-yl)benzoate;N-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N′-(tetrahydrofuran-3-yl)sulfamide;tert-butyl4-[4-(7-{[(3-methylpyridin-2-yl)methyl]amino}-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-3-yl)phenyl]piperazine-1-carboxylate;7-{[(3-methylpyridin-2-yl)methyl]amino}-3-(4-piperazin-1-ylphenyl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;3-[3-(dimethylamino)phenyl]-7-{[(3-methylpyridin-2-yl)methyl]amino}-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;7-{[(3-methylpyridin-2-yl)methyl]amino}-3-pyridin-4-yl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;N-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N′-(tetrahydrofuran-3-ylmethyl)sulfamide;N-[(1-methyl-1H-pyrazol-4-yl)methyl]-N′-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]sulfamide;N-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]morpholine-4-sulfonamide;N-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-2-(trifluoromethyl)-5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-sulfonamide;N-isobutyl-4-(7-{[(3-methylpyridin-2-yl)methyl]amino}-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-3-yl)benzamide;7-{[(3-methylpyridin-2-yl)methyl]amino}-3-pyrimidin-5-yl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;4-(7-{[(3-methylpyridin-2-yl)methyl]amino}-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-3-yl)-N-phenylbenzamide;3-(6-fluoropyridin-3-yl)-7-{[(3-methylpyridin-2-yl)methyl]amino}-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;N-[3-(dimethylamino)propyl]-4-(7-{[(3-methylpyridin-2-yl)methyl]amino}-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-3-yl)benzamide;3-(1-methyl-1H-pyrazol-4-yl)-7-[(tetrahydro-2H-pyran-4-ylmethyl)amino]-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;3-pyridin-4-yl-7-[(tetrahydro-2H-pyran-4-ylmethyl)amino]-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;7-[(1,4-dioxan-2-ylmethyl)amino]-3-(1-methyl-1H-pyrazol-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;N-[3-(4-isopropylpiperazin-1-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;3-(4-isopropylpiperazin-1-yl)-7-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;N-(5-oxo-3-piperidin-1-yl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)methanesulfonamide;N-(3-morpholin-4-yl-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)methanesulfonamide;N-(5-oxo-3-pyrrolidin-1-yl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)methanesulfonamide;N-[3-(benzylamino)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;N-{3-[(2,4-dimethoxybenzyl)amino]-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl}methanesulfonamide;N-{3-[butyl(methyl)amino]-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl}methanesulfonamide;N-{3-[(cyclopropylmethyl)amino]-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl}methanesulfonamide;N-(3-amino-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)methanesulfonamide;N,N′-(5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-3,7-diyl)dimethanesulfonamide;N-(3-anilino-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)methanesulfonamide;N-[3-(cyclohexylamino)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;N-[5-oxo-3-(pyridin-4-ylamino)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;N-[5-oxo-3-(pyridin-3-ylamino)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;N-[5-oxo-3-(pyridin-2-ylamino)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;tert-butyl4-{7-[(methylsulfonyl)amino]-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-3-yl}piperazine-1-carboxylate;N-[3-(4-methylpiperazin-1-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;N-[3-(1,4-dioxa-8-azaspiro[4,5]dec-8-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;N-[5-oxo-3-(4-quinolin-2-ylpiperazin-1-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;N-{3-[(4-chlorobenzyl)amino]-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl}methanesulfonamide;N-{5-oxo-3-[(1-phenylethyl)amino]-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl}methanesulfonamide;N-{3-[(2-morpholin-4-ylethyl)amino]-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl}methanesulfonamide;N-{5-hydroxy-3-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl}methanesulfonamide;N-(3-chloro-5-hydroxy-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)methanesulfonamide;N-(3-{4-[(2-methyl-1,3-thiazol-4-yl)methyl]piperazin-1-yl}-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)methanesulfonamide;N-{3-[4-(4-chloropyridin-2-yl)piperazin-1-yl]-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl}methanesulfonamide;N-{5-oxo-3-[4-(pyridin-3-ylmethyl)piperazin-1-yl]-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl}methanesulfonamide;N-(5-oxo-3-piperazin-1-yl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)methanesulfonamide;N-{5-oxo-3-[4-(pyridin-2-ylmethyl)piperazin-1-yl]-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl}methanesulfonamide;N-[5-oxo-3-(4-pyridin-3-ylpiperazin-1-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;N-{5-oxo-3-[2-(trifluoromethyl)-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl]-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl}methanesulfonamide;N-(3-{4-[3,5-bis(trifluoromethyl)phenyl]piper-azin-1-yl}-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)methanesulfonamide;N-{3-[(1-methyl-1H-pyrazol-3-yl)amino]-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl}methanesulfonamide;7-[(2,4-dimethoxybenzyl)amino]-3-(1,4-dioxa-8-azaspiro[4,5]dec-8-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;7-[(2,4-dimethoxybenzyl)amino]-3-(4-isopropylpiperazin-1-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;3-(4-isopropylpiperazin-1-yl)-7-morpholin-4-yl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;3-(4-acetylpiperazin-1-yl)-7-morpholin-4-yl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;3-(4-isopropylpiperazin-1-yl)-7-[(1-phenylethyl)amino]-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;7-anilino-3-(4-isopropylpiperazin-1-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;7-(benzylamino)-3-(4-isopropylpiperazin-1-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;4-[7-(benzylamino)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-3-yl]-N,N-dimethylpiperazine-1-carboxamide;7-(tert-butylamino)-3-(4-isopropylpiperazin-1-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;3-(4-isopropylpiperazin-1-yl)-7-[(2-methoxyethyl)amino]-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;3-(4-isopropylpiperazin-1-yl)-7-[(3-methoxypropyl)amino]-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;7-[(1-ethylpropyl)amino]-3-(4-isopropylpiperazin-1-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;7-[(1-ethylpropyl)amino]-3-(4-methyl-1,4-diazepan-1-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;7-[(3-methoxypropyl)amino]-3-(4-methyl-1,4-diazepan-1-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;7-amino-3-(4-isopropylpiperazin-1-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;7-amino-3-(4-oxopiperidin-1-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;7-hydroxy-3-(4-isopropylpiperazin-1-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;3-(4-isopropylpiperazin-1-yl)-7-piperidin-1-yl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;3,7-bis{[(3-methylpyridin-4-yl)methyl]amino}-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;N-(3-chloro-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)-2-methoxyacetamide;ethyl(5-oxo-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-8-yl)carbamate;N-ethyl-N′-(5-oxo-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-8-yl)urea;N-(2,4-dimethoxybenzyl)-N-(5-oxo-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)ethylenesulfonamide;N-(5-oxo-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)ethylenesulfonamide;N-(5-oxo-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)-2-pyrrolidin-1-ylethanesulfonamide;N-methyl-N-(5-oxo-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)methanesulfonamide;3-chloro-7-[(2,4-dimethoxybenzyl)(methyl)amino]-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;dimethyl[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]amidophosphate;N,N-(5-oxo-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)bis-methanesulfonamide;N,N-(5-oxo-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)bis-benzenesulfonamide;N-(5-oxo-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)benzenesulfonamide;N-(5-oxo-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)ethanesulfonamide;N-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]propane-2-sulfonamide;2-chloro-N-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]propane-2-sulfinamide;N-(5-oxo-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)-2-phenylacetamide;2-methoxy-N-(5-oxo-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)acetamide;N-acetyl-N′-(5-oxo-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-9-yl)acetamide;N-[3-(4-isopropylpiperazin-1-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-2-methoxyacetamide;N-[3-(1,4-dioxa-8-azaspiro[4,5]dec-8-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-2-methoxyacetamide;2-methoxy-N-[5-oxo-3-(3-thienyl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]acetamide;2-{[(3-chloro-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)amino]carbonyl}benzoicacid; ethyl[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]carbamate;N-ethyl-N′-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]urea;7-amino-3-(1,4-dioxa-8-azaspiro[4,5]dec-8-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;2-(diethylamino)-N-(5-oxo-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)ethanesulfonamide;2-morpholin-4-yl-N-(5-oxo-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)ethanesulfonamide;2-(1H-imidazol-1-yl)-N-(5-oxo-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)ethanesulfonamide;2-[(2,4-dimethoxybenzyl)amino]-N-(5-oxo-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)ethanesulfonamide;2-[(2-morpholin-4-ylethyl)amino]-N-(5-oxo-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)ethanesulfonamide;2-(benzylamino)-N-(5-oxo-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)ethanesulfonamide;2-(dimethylamino)-N-(5-oxo-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)ethanesulfonamide;N-(5-oxo-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)-2-(1H-pyrazol-1-yl)ethanesulfonamide;N-(3-chloro-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)-2-(1H-imidazol-1-yl)ethanesulfonamide;N-[3-(1,4-dioxa-8-azaspiro[4,5]dec-8-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-2-(1H-imidazol-1-yl)ethanesulfonamide;7-(methylamino)-3-(1-methyl-1H-pyrazol-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;N-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]sulfamide;tert-butyl({[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]amino}sulfonyl)carbamate;N-(5-hydroxy-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)methanesulfonamide;7-[(methylsulfonyl)amino]-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-ylacetate;N-(5-methoxy-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)-N-methylmethanesulfonamide;N-(3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)methanesulfonamide;N-[(5E/Z)-5-(hydroxyimino)-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;N-(3-phenyl-5-pyrrolidin-1-yl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)methanesulfonamide;N-[(5E/Z)-5-(methoxyimino)-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;N-[(5E/Z)-5-(tert-butoxyimino)-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;(5E/Z)-7-amino-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-oneoxime;N-[5-(dimethylamino)-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;N-[5-(isopropylamino)-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;N-[5-(cyclopropylamino)-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;N-[5-(benzylamino)-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;N-(5-azetidin-1-yl-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)methanesulfonamide;N-(3-phenyl-5-piperidin-1-yl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)methanesulfonamide;N-(5-morpholin-4-yl-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)methanesulfonamide;7-[(methylsulfonyl)amino]-3-phenyl-5-piperazinediium-1-yl-5H-benzo[4,5]cyclohepta[1,2-b]pyridine;7-(hydroxymethyl)-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-ol;7-({[tert-butyl(dimethyl)silyl]oxy}methyl)-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-ol;7-({[tert-butyl(dimethyl)silyl]oxy}methyl)-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;7-(hydroxymethyl)-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;7-({[tert-butyl(dimethyl)silyl]oxy}methyl)-3-chloro-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;7-({[tert-butyl(dimethyl)silyl]oxy}methyl)-3-(1-methyl-1H-pyrazol-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;7-(hydroxymethyl)-3-(1-methyl-1H-pyrazol-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methylacetate;[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methylbenzoate;7-[(methylsulfonyl)methyl]-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;(5-oxo-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)methylmethanesulfinate;7-(aminomethyl)-3-(1-methyl-1H-pyrazol-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;N-{[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methyl}methanesulfonamide;N-(5-oxo-3-phenyl-10,11-dihydro-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)methanesulfonamide;7-amino-6-chloro-3-(1-methyl-1H-pyrazol-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;methyl7-{[(dimethylamino)sulfonyl]amino}-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-3-carboxylate;7-{[(dimethylamino)sulfonyl]amino}-5-oxo-N-1,3-thiazol-2-yl-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-3-carboxamide;3-chloro-7-vinyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;3-chloro-7-oxiran-2-yl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;3-chloro-7-(1-hydroxyethyl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-ol;3-chloro-7-(2-hydroxyethyl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-ol;7-(1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-3-chloro-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;7-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-3-chloro-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;7-(1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-3-(1-methyl-1H-pyrazol-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;7-[(1R)-1-hydroxyethyl]-3-(1-methyl-1H-pyrazol-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;7-[(1S)-1-hydroxyethyl]-3-(1-methyl-1H-pyrazol-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;7-(2-hydroxyethyl)-3-(1-methyl-1H-pyrazol-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;3-chloro-7-(1-hydroxyethyl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;3-chloro-7-ethyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-ol;3-chloro-7-(1,2-dihydroxyethyl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;7-(1,2-dihydroxyethyl)-3-(1-methyl-1H-pyrazol-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;3-chloro-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-7-carbaldehyde;3-chloro-7-(1-hydroxypropyl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;7-[(1R)-1-methoxyethyl]-3-(1-methyl-1H-pyrazol-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;7-[(1S)-1-methoxyethyl]-3-(1-methyl-1H-pyrazol-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;tert-butyl4-[2-(3-chloro-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)-2-hydroxyethyl]piperazine-1-carboxylate;tert-butyl4-{2-hydroxy-2-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]ethyl}piperazine-1-carboxylate;7-(1-hydroxy-2-piperazin-1-ylethyl)-3-(1-methyl-1H-pyrazol-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;7-[(2-morpholin-4-yl-2-oxoethyl)amino]-3-[1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl]-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;3-(1-methyl-1H-pyrazol-4-yl)-7-{[2-(3-oxomorpholin-4-yl)ethyl]amino}-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;3-fluoro-N-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]azetidine-1-sulfonamide;N-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]azetidine-1-sulfonamide;N-(2-fluoro-3-methoxypropyl)-N-methyl-N′-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]sulfamide7-(2,2-difluoro-1-hydroxyethyl)-3-(1-methyl-1H-pyrazol-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one7-(2,2-difluoro-1(R)-hydroxyethyl)-3-(1-methyl-1H-pyrazol-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one7-(2,2-difluoro-1-hydroxyethyl)-3-(1-methyl-1H-pyrazol-4-yl)-5H-benzo[4,5]cyclohepta1,2-b]pyridin-5-one 7-(2,2-difluoro-1(S)-hydroxyethyl)-3-(1-methyl-1H-pyrazol-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-oneN-(1,4-dioxan-2-ylmethyl)-N′-[6-fluoro-3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-methylsulfamide;N-(1,4-dioxan-2-ylmethyl)-N′-[8-fluoro-3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-methylsulfamide;6-fluoro-7-(2-fluoro-1-hydroxyethyl)-3-(1-methyl-1H-pyrazol-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;7-[(2-morpholin-4-yl-2-oxoethyl)amino]-3-[1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl]-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;3-(1-methyl-1H-pyrazol-4-yl)-7-{[2-(3-oxomorpholin-4-yl)ethyl]amino}-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;3-fluoro-N-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]azetidine-1-sulfonamide;N-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]azetidine-1-sulfonamide;3-(1-methyl-1H-pyrazol-4-yl)-7-[(2-morpholin-4-yl-2-oxoethyl)amino]-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;N-(2-fluoro-3-methoxypropyl)-N-methyl-N′-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]sulfamide7-(2,2-difluoro-1-hydroxyethyl)-3-(1-methyl-1H-pyrazol-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one7-(2,2-difluoro-1(R)-hydroxyethyl)-3-(1-methyl-1H-pyrazol-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one7-(2,2-difluoro-1-hydroxyethyl)-3-(1-methyl-1H-pyrazol-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one7-(2,2-difluoro-1(S)-hydroxyethyl)-3-(1-methyl-1H-pyrazol-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-oneN-(1,4-dioxan-2-ylmethyl)-N′-[6-fluoro-3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-methylsulfamide;N-(1,4-dioxan-2-ylmethyl)-N′-[8-fluoro-3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-methylsulfamide;6-fluoro-7-(2-fluoro-1-hydroxyethyl)-3-(1-methyl-1H-pyrazol-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one;or a pharmaceutically acceptable salt or stereoisomer thereof.
 5. Apharmaceutical composition that is comprised of a compound in accordancewith claim 1 and a pharmaceutically acceptable carrier.
 6. A method oftreating or preventing cancer in a mammal in need of such treatment thatis comprised of administering to said mammal a therapeutically effectiveamount of a compound of claim
 1. 7. A method of treating cancer orpreventing cancer in accordance with claim 6 wherein the cancer isselected from cancers of the brain, genitourinary tract, lymphaticsystem, stomach, larynx and lung.
 8. A method of treating or preventingcancer in accordance with claim 6 wherein the cancer is selected fromhistiocytic lymphoma, lung adenocarcinoma, small cell lung cancers,pancreatic cancer, liver cancer, gastric cancer, colon cancer, multiplemyeloma, glioblastomas and breast carcinoma.
 9. A method of using thecompound according to claim 1 for the preparation of a medicament usefulin treating or preventing cancer in a mammal in need of such treatment.10. A method of using the compound according to claim 1 for thepreparation of a medicament useful in inhibiting the receptor tyrosinekinase MET in a mammal in need of such treatment.
 11. A method of usingthe compound according to claim 1 for the preparation of a medicamentuseful in preventing or modulating metastasis of cancer in a mammal inneed of such treatment.
 12. The method of using the compound inaccordance with claim 11 wherein the cancer is selected from ovariancancer, childhood hepatocellular carcinoma, metastatic head and necksquamous cell carcinomas, gastric cancer, breast cancer, colorectalcancer, cervical cancer, lung cancer, nasopharyngeal cancer, pancreaticcancer, glioblastoma and sarcomas.